TEAD inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 62/855,082, filed May 31, 2019; U.S.Provisional Patent Application No. 62/928,931, filed Oct. 31, 2019; U.S.Provisional Patent Application No. 62/944,567, filed Dec. 6, 2019; andU.S. Provisional Patent Application No. 63/025,336, filed May 15, 2020,the contents of each of which are herein incorporated by reference intheir entireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 23, 2020, isnamed 174045_SL.txt and is 23,666 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibition of Transcriptional Enhancer Associate Domain (TEAD). Theinvention also provides pharmaceutically acceptable compositionscomprising compounds of the present invention and methods of using saidcompositions in the treatment of various diseases, disorders, andconditions as described herein.

BACKGROUND OF THE INVENTION

Yes-associated protein (YAP) and transcriptional co-activator withPDZ-binding motif (TAZ) are transcriptional co-activators of the Hippopathway network and regulate cell proliferation, migration, andapoptosis. Inhibition of the Hippo pathway promotes YAP/TAZtranslocation to the nucleus, wherein YAP/TAZ interact with TEADtranscription factors and coactivate the expression of target genes andpromote cell proliferation. Hyperactivation of YAP and TAZ and/ormutations in one or more members of the Hippo pathway network have beenimplicated in numerous cancers.

SUMMARY OF THE INVENTION

The Hippo signaling cascade is an important pathway for cancerbiogenesis and tumor maintenance. The Hippo pathway is heavily mutatedacross many cancer indications through loss of function mutations ingenes such as NF2. These pro-tumor mutations lead to the constitutiveactivation of the downstream transcriptional coactivators YAP and TAZthat drive the expression of many pro-survival and proliferation genesthrough the essential interaction with a TEAD protein family member. Inaddition, this unrestrained transcriptional program drives enhancedimmune suppression in the tumor microenvironment. As described herein,to target this oncogenic pathway novel small molecule inhibitors wereidentified that selectively bind to TEAD and disrupt their interactionwith YAP and TAZ, thereby downregulating YAP- and TAZ-dependenttranscription. As demonstrated herein, these TEAD inhibitors preventTEAD palmitoylation, which is critical for the interaction between YAPand TEAD. Furthermore, the TEAD inhibitors described herein inhibit invitro proliferation of YAP-dependent (i.e., Hippo pathway-deficientcancer cell lines), but not Hippo pathway wild type cancer cell lines.Importantly, as shown herein, the TEAD inhibitor compounds of thepresent invention did not affect survival of a differentiated mousepodocyte cell line or compromise mouse kidney histology. Subsequentexperiments in vivo demonstrate the TEAD inhibitors described hereindownregulate YAP-dependent genes in human tumor xenografts after oraldosing. In addition, the TEAD inhibitors described herein exhibit singleagent tumor growth inhibition of human tumor xenografts in mice at welltolerated oral doses. The data described herein demonstrate the abilityof the small molecule TEAD inhibitors provided herein for targeting theHippo pathway in cancers.

It has now been found that compounds of the present invention, andpharmaceutically acceptable compositions thereof, are effective as TEADinhibitors. In one aspect, the present invention provides a compound ofFormula I′:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein. In one aspect, the present inventionprovides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablesalts and compositions thereof, are useful for treating a variety ofdiseases, disorders or conditions associated with TEAD. Such diseases,disorders, or conditions include cellular proliferative disorders (e.g.,cancer as described herein).

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts a schematic of Hippo pathway signaling.

FIG. 2 demonstrates inhibition of cell growth of an NF2 mutant cell lineby isomer 2 of compound I-12. The effect of isomer 2 of compound I-12 oncell proliferation is dependent on the presence of a Hippo/NF2 mutation.No effect is seen by isomer 2 of compound I-12 on the NF2 wild-type H28cell line.

FIG. 3 shows anti-proliferative effects of isomer 2 of compound I-12 asevaluated in a 3-day Cell TITERGLO™ assay. The cell lines were chosenbased on Cancer Dependency score and a sampling of known interactingoncogenes. Cell lines with an EC50<0.2 μM or <1.0 μM are indicated byboxes. EC50 values were calculated from inflection points.

FIG. 4 depicts pharmacokinetic (PK) properties of isomer 1 of compoundI-186 following dosing in BALB/c mice.

FIG. 5 depicts pharmacodynamic (PD) properties of isomer 2 of compoundI-12 and isomer 1 of compound I-186 using real-time PCR.

FIGS. 6A-6B demonstrate anti-tumor activities of isomer 2 of compoundI-12 (6A) and isomer 1 of compound I-186 (6B) in an H226 mesotheliomaxenograft model. No effects were observed on body weights throughoutstudies. Kidneys at end of studies showed no signs of damage byhistopathology.

FIG. 7 demonstrates anti-tumor activities of isomer 2 of compound I-12and isomer 1 of compound I-186 in an MSTO-211H mesothelioma xenograftmodel. No effects were observed on body weights throughout studies.Kidneys at end of studies showed no signs of damage by histopathology.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and pharmaceutical salts andcompositions thereof, are useful as inhibitors of TEAD. Without wishingto be bound by any particular theory, it is believed that compounds ofthe present invention, and pharmaceutical compositions thereof, inhibitthe activity of TEAD, and thus treat diseases, disorders or conditionsassociated with TEAD, such as cancer.

In one aspect, the present invention provides a compound of Formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is C₁₋₆ bivalent straight or branched hydrocarbon chain wherein    1, 2, or 3 methylene units of the chain are independently and    optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—,    —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—,    —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—,    —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—,    —(R)NC(S)—, or —(R)NC(S)N(R)—;-   Ring A is an optionally substituted ring selected from phenyl, a 4-,    5-, or 6-membered saturated or partially unsaturated monocyclic    carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5-6    membered monocyclic heteroaromatic ring having 1, 2, 3, or 4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur;-   Ring B is an optionally substituted ring selected from phenyl, a 4-,    5-, or 6-membered saturated or partially unsaturated monocyclic    carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5-6    membered monocyclic heteroaromatic ring having 1, 2, 3, or 4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur;-   R^(w) is a warhead group; wherein when R^(w) is a saturated or    partially unsaturated monocyclic carbocyclic or heterocyclic ring,    it optionally forms a spiro bicyclic ring with Ring B; and    each R is independently —H or optionally substituted —C₁₋₆    aliphatic.

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is C₁₋₆ bivalent straight or branched hydrocarbon chain wherein    1, 2, or 3 methylene units of the chain are independently and    optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—,    —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—,    —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—,    —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—,    —(R)NC(S)—, or —(R)NC(S)N(R)—;-   Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated    monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6-membered    saturated or partially unsaturated monocyclic heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having    1, 2, 3, or 4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, wherein Ring A is optionally substituted 1-2    times by -halogen, —CN, —NO₂—, or —C₁₋₆ aliphatic substituted 0-6    times by -halogen, —CN, or —NO₂;-   R² is —H, or a warhead group;-   R³ is —H or a warhead group;-   R⁴ is —H, halogen, —S(O)₂N(R)₂—, —S(O)N(R)₂—, —C(O)N(R)₂—, or a    warhead group;-   R⁶ is —H or —C₁₋₆ aliphatic substituted 0-6 times by -halogen, —CN,    or —NO₂; and    each R is independently —H or optionally substituted —C₁₋₆    aliphatic.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bicyclic ring” or “bicyclic ring system”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or having one or more units of unsaturation, having one ormore atoms in common between the two rings of the ring system. Thus, theterm includes any permissible ring fusion, such as ortho-fused orspirocyclic. As used herein, the term “heterobicyclic” is a subset of“bicyclic” that requires that one or more heteroatoms are present in oneor both rings of the bicycle. Such heteroatoms may be present at ringjunctions and are optionally substituted, and may be selected fromnitrogen (including N-oxides), oxygen, sulfur (including oxidized formssuch as sulfones and sulfonates), phosphorus (including oxidized formssuch as phosphates), boron, etc. In some embodiments, a bicyclic grouphas 7-12 ring members and 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or partially unsaturated, having at least one bridge. Asdefined by IUPAC, a “bridge” is an unbranched chain of atoms or an atomor a valence bond connecting two bridgeheads, where a “bridgehead” isany skeletal atom of the ring system which is bonded to three or moreskeletal atoms (excluding hydrogen). In some embodiments, a bridgedbicyclic group has 7-12 ring members and 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groupsare well known in the art and include those groups set forth below whereeach group is attached to the rest of the molecule at any substitutablecarbon or nitrogen atom. Unless otherwise specified, a bridged bicyclicgroup is optionally substituted with one or more substituents as setforth for aliphatic groups. Additionally or alternatively, anysubstitutable nitrogen of a bridged bicyclic group is optionallysubstituted. Exemplary bicyclic rings include:

Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Each optional substituent on a substitutable carbon is a monovalentsubstituent independently selected from halogen; —(CH₂)₀₋₄R^(o);—(CH₂)₀₋₄R^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(R^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄C(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o); —(CH₂)₀₋₄C(O)NR⁰²;—C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o), —(CH₂)₀₋₄C(O)NR⁰²;—C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR⁰²;—S(O)(NR^(o))R^(o); —S(O)₂N═C(NR^(o) ₂)₂; —(CH₂)₀₋₄S(O)R^(o);—N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o); —N(OR^(o))R^(o);—C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o) ₂;—OP(O)(OR^(o))₂; SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂.

Each R^(o) is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted by a divalentsubstituent on a saturated carbon atom of R^(o) selected from ═O and ═S;or each R^(o) is optionally substituted with a monovalent substituentindependently selected from halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂—, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂—, —NO₂—, —SiR^(•) ₃, —OSiR^(•)3, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•).

Each R^(•) is independently selected from C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and wherein each R^(•) is unsubstituted or wherepreceded by halo is substituted only with one or more halogens; orwherein an optional substituent on a saturated carbon is a divalentsubstituent independently selected from ═O, ═S, ═NNR^(•) ₂—, ═NNHC(O)R*,═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R^(•) ₂))₂₋₃O—, or—S(C(R^(•) ₂))₂₋₃S—, or a divalent substituent bound to vicinalsubstitutable carbons of an “optionally substituted” group is —O(CR^(•)₂)₂₋₃O—, wherein each independent occurrence of R* is selected fromhydrogen, C₁₋₆ aliphatic or an unsubstituted 5-6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

When R* is C₁₋₆ aliphatic, R* is optionally substituted with halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂—, —NHR^(•), —NR^(•) ₂—, or —NO₂—, wherein each R^(•)is independently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, andwherein each R^(•) is unsubstituted or where preceded by halo issubstituted only with one or more halogens.

An optional substituent on a substitutable nitrogen is independently—R^(†), —NR^(†) ₂—, —C(O)R^(†), —C(O)OR^(†), —C(O)C(O)R^(†),—C(O)CH₂C(O)R^(†), —S(O)₂R, —S(O)₂NR₂—, —C(S)NR^(†) ₂—, —C(NH)NR^(†) ₂—,or —N(R^(†))S(O)₂R; wherein each R is independently hydrogen, C₁₋₆aliphatic, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or, twoindependent occurrences of R, taken together with their interveningatom(s) form an unsubstituted 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; wherein when Ris C₁₋₆ aliphatic, R is optionally substituted with halogen, —R^(•),-(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH, —C(O)O^(•),—NH₂—, —NHR^(•), —N^(•) ₂—, or —NO₂—, wherein each R^(•) isindependently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, andwherein each R^(•) is unsubstituted or where preceded by halo issubstituted only with one or more halogens.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety of a provided compound comprises one ormore deuterium atoms.

As used herein, the terms “inhibitor” or “TEAD inhibitor” or “TEADantagonist” are defined as a compound that binds to and/or inhibits TEADwith measurable affinity. In some embodiments, inhibition in thepresence of the inhibitor is observed in a dose-dependent manner. Insome embodiments, the measured signal (e.g., signaling activity orbiological activity) is at least about 5%, at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, at least about 96%,at least about 97%, at least about 98%, at least about 99%, or at leastabout 100% lower than the signal measured with a negative control undercomparable conditions. The potency of an inhibitor is usually defined byits IC₅₀ value (half maximal inhibitory concentration or concentrationrequired to inhibit 50% of the agonist response). The lower the IC₅₀value the greater the potency of the antagonist and the lower theconcentration that is required to inhibit the maximum biologicalresponse. In certain embodiments, an inhibitor has an IC₅₀ and/orbinding constant of less than about 100 μM, less than about 50 μM, lessthan about 1 μM, less than about 500 nM, less than about 100 nM, lessthan about 10 nM, or less than about 1 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change or inhibition in TEAD activity betweena sample comprising a compound of the present invention, or compositionthereof, and TEAD, and an equivalent sample comprising TEAD, in theabsence of said compound, or composition thereof.

3. Description of Exemplary Embodiments

In one aspect, the present invention provides a compound of Formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is a covalent bond, or a C₁₋₆ bivalent straight or branched    hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain    are independently and optionally replaced with —O—, —CH(OR)—,    —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—,    —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—,    —SO₂—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—,    —(R)NC(S)—, or —(R)NC(S)N(R)—;-   Ring A is an optionally substituted ring selected from phenyl, a 4-,    5-, or 6-membered saturated or partially unsaturated monocyclic    carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5-6    membered monocyclic heteroaromatic ring having 1, 2, 3, or 4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur;-   Ring B is an optionally substituted ring selected from phenyl, a 4-,    5-, or 6-membered saturated or partially unsaturated monocyclic    carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5-6    membered monocyclic heteroaromatic ring having 1, 2, 3, or 4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur;-   R^(w) is a warhead group; wherein when R^(w) is a saturated or    partially unsaturated monocyclic carbocyclic or heterocyclic ring,    it optionally forms a spiro bicyclic ring with Ring B; and    each R is independently —H or optionally substituted —C₁₋₆    aliphatic.

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is C₁₋₆ bivalent straight or branched hydrocarbon chain wherein    1, 2, or 3 methylene units of the chain are independently and    optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—,    —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—,    —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—,    —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—,    —(R)NC(S)—, or —(R)NC(S)N(R)—;-   Ring A is a 4-, 5-, or 6-membered saturated or partially unsaturated    monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6-membered    saturated or partially unsaturated monocyclic heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having    1, 2, 3, or 4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, wherein Ring A is optionally substituted 1-2    times by halogen, —CN, —NO₂—, or —C₁₋₆ aliphatic substituted 0-6    times by halogen, —CN, or —NO₂;-   R² is —H, or a warhead group;-   R³ is —H or a warhead group;-   R⁴ is —H, halogen, —S(O)₂N(R)₂—, —S(O)N(R)₂—, —C(O)N(R)₂—, or a    warhead group;-   R⁶ is —H or —C₁₋₆ aliphatic substituted 0-6 times by halogen, —CN,    or —NO₂; and    each R is independently —H or optionally substituted —C₁₋₆    aliphatic.

As defined generally above, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—,—CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—,—OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,—(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or—(R)NC(S)N(R)—.

In some embodiments, L¹ is a covalent bond, or a C₁₋₆ bivalent straightor branched hydrocarbon chain wherein 1, 2, or 3 methylene units of thechain are independently and optionally replaced with —O—, —CH(OR)—,—CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—,—(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—,—SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—,or —(R)NC(S)N(R)—.

In some embodiments, L¹ is a covalent bond.

In some embodiments, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently and optionally replaced with —O—, —CH(OR)—, —CH(N(R)₂)—,—C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,—(R)NC(O)O—, or —N(R)C(O)N(R)—.

In some embodiments, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areoptionally replaced with —CH(SR)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,—(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or—(R)NC(S)N(R)—.

In some embodiments, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently and optionally replaced with —O—, —S—, or —N(R)—.

In some embodiments, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently and optionally replaced with —CH(OR)—, —CH(SR)—, or—CH(N(R)₂)—.

In some embodiments, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently and optionally replaced with —(O)—, —C(O)O—, —OC(O)—,—SO—, —SO₂—, —C(S)—, —C(S)O—, or —OC(S)—.

In some embodiments, L¹ is C₁₋₆ bivalent straight or branchedhydrocarbon chain wherein 1, 2, or 3 methylene units of the chain areindependently and optionally replaced with —(O)N(R)—, —(R)NC(O)—,—OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —SO₂N(R)—, —(R)NSO₂—,—C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹ is —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—,—C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,—(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO₂—, —SO₂N(R)—, —(R)NSO₂—,—C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—.

In some embodiments, L¹ is —O—, —CH(OR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—,—OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, or—N(R)C(O)N(R)—.

In some embodiments, L¹ is —CH(SR)—, —S—, —SO—, —SO₂—, —SO₂N(R)—,—(R)NSO₂—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or—(R)NC(S)N(R)—.

In some embodiments, L¹ is —O—, —S—, or —N(R)—. In some embodiments, L¹is —O—. In some embodiments, L¹ is —S—. In some embodiments, L¹ is—N(R)—. In some embodiments, L¹ is —NH—.

In some embodiments, L¹ is —CH(OR)—, —CH(SR)—, or —CH(N(R)₂)—. In someembodiments, L¹ is —CH(OR)—. In some embodiments, L¹ is —CH(SR)—. Insome embodiments, L¹ is —CH(N(R)₂)—.

In some embodiments, L¹ is —C(O)—, —C(O)O—, —OC(O)—, —SO—, —SO₂—,—C(S)—, —C(S)O—, or —OC(S)—. In some embodiments, L¹ is —C(O)—. In someembodiments, L¹ is —C(O)O—. In some embodiments, L¹ is —OC(O)—. In someembodiments, L¹ is —SO—. In some embodiments, L¹ is —SO₂—. In someembodiments, L¹ is —C(S)—. In some embodiments, L¹ is —C(S)O—. In someembodiments, L¹ is —OC(S)—.

In some embodiments, L¹ is —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—,—(R)NC(O)O—, —N(R)C(O)N(R)—, —SO₂N(R)—, —(R)NSO₂—, —C(S)N(R)—,—(R)NC(S)—, or —(R)NC(S)N(R)—. In some embodiments, L¹ is —C(O)N(R)—. Insome embodiments, L¹ is —(R)NC(O)—. In some embodiments, L¹ is—OC(O)N(R)—. In some embodiments, L¹ is —(R)NC(O)O—. In someembodiments, L¹ is —N(R)C(O)N(R)—. In some embodiments, L¹ is —SO₂N(R)—.In some embodiments, L¹ is —(R)NSO₂—. In some embodiments, L¹ is—C(S)N(R)—. In some embodiments, L¹ is —(R)NC(S)—, or In someembodiments, L¹ is —(R)NC(S)N(R)—.

In some embodiments, L¹ is —CH₂—, —CH(CH₃)—, —NH—CH₂—, —NH—CH(CH₃)—,—C(O)—NH—, or —N(CH₃)—.

In some embodiments, L¹ is

In some embodiments, L¹ is selected from the corresponding L¹ moietiesin those compounds depicted in Table 1, below.

As defined generally above, Ring A is a 4-, 5-, or 6-membered saturatedor partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-,or 6-membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ringhaving 1, 2, 3, or 4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times byhalogen, —CN, —NO₂—, or —C₁₋₆ aliphatic substituted 0-6 times byhalogen, —CN, or —NO₂.

In some embodiments, Ring A is an optionally substituted ring selectedfrom phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4heteroatoms independently selected from nitrogen, oxygen, or sulfur, a8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring A is optionally substituted phenyl. In someembodiments, Ring A is optionally substituted 4-, 5-, or 6-memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, Ring A is optionally substituted 4-, 5-, or 6-memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, Ring A is optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is optionally substituted 8-10 membered bicyclicaromatic ring. In some embodiments, Ring A is optionally substituted8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is optionally substituted phenyl, a6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a10-membered bicyclic heteroaromatic ring having 1-2 nitrogen.

In some embodiments, Ring A is optionally substituted

In some embodiments, Ring A is optionally substituted 1-2 times by-halogen, —CN, —NO₂—, —C₁₋₆ aliphatic, or —O—C₁₋₆ aliphatic, whereineach of —C₁₋₆ aliphatic and —O—C₁₋₆ aliphatic is independentlysubstituted 0-6 times by -halogen, —CN, or —NO₂. In some embodiments,Ring A is optionally substituted 1-2 times by halogen, —CN, —NO₂—, —C₁₋₆aliphatic, or —O—C₁₋₆ aliphatic, wherein each of —C₁₋₆ aliphatic and—O—C₁₋₆ aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6times by halogen, —CN, or —NO₂. In some embodiments, Ring A isoptionally substituted 1-2 times by halogen, —C₁₋₆ aliphatic, or —O—C₁₋₆aliphatic, wherein each of —C₁₋₆ aliphatic and —O—C₁₋₆ aliphatic isindependently substituted 1, 2, 3, 4, 5, or 6 times by halogen.

In some embodiments, Ring A is a 4-, 5-, or 6-membered saturated orpartially unsaturated monocyclic carbocyclic ring. In some embodiments,Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In someembodiments, Ring A is a 4-, 5-, or 6-membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ringhaving 1, 2, 3, or 4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, Ring A is a 8-10 membered bicyclic aromatic ring.In some embodiments, Ring A is a 8-10 membered bicyclic heteroaromaticring having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, Ring A is optionally substituted 1-2 times byhalogen, —CN, —NO₂—, or —C₁₋₆ aliphatic substituted 0, 1, 2, 3, 4, 5, or6 times by halogen, —CN, or —NO₂. In some embodiments, Ring A isoptionally substituted 1-2 times by halogen, or —C₁₋₆ aliphaticsubstituted 0, 1, 2, 3, 4, 5, or 6 times by halogen.

In some embodiments, Ring A is selected from

wherein each of R¹ and R⁷ is independently as described herein.

In some embodiments, Ring A is selected from

In some embodiments, R¹ is —H, -halogen, —CN, —NO₂—, —C₁₋₆ aliphatic, or—O—C₁₋₆ aliphatic, wherein each of —C₁₋₆ aliphatic and —O—C₁₋₆ aliphaticis substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂.In some embodiments, R¹ is unsubstituted —O—C₁₋₆ aliphatic. In someembodiments, R¹ is —OCH₃. In some embodiments, R¹ is —O—C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments,R¹ is —O—C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by-halogen. In some embodiments, R¹ is —O—C₁₋₆ aliphatic substituted 1, 2,3, 4, 5, or 6 times by —F.

In some embodiments, R¹ is —H, -halogen, —CN, —NO₂—, or —C₁₋₆ aliphaticsubstituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. Insome embodiments, R¹ is —H. In some embodiments, R¹ is -halogen. In someembodiments, R¹ is —F. In some embodiments, R¹ is —Cl. In someembodiments, R¹ is —Br. In some embodiments, R¹ is —CN. In someembodiments, R¹ is —NO₂. In some embodiments, R¹ is unsubstituted —C₁₋₆aliphatic. In some embodiments, R¹ is —CH₃. In some embodiments, R¹ is—C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. Insome embodiments, R¹ is —C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6times by -halogen. In some embodiments, R¹ is —C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R¹ is—C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In someembodiments, R¹ is —CF₃. In some embodiments, R¹ is —C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by —CN. In some embodiments, R¹ is—C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —NO₂.

In some embodiments, R¹ is phenyl. In some embodiments, R¹ is —C(CH₃)₃.In some embodiments, R¹ is —SCF₃. In some embodiments, R¹ is —S(O)₂CF₃.In some embodiments, R¹ is —N(CH₃)₂. In some embodiments, R¹ is —CHF₂.In some embodiments, R¹ is cyclopropyl. In some embodiments, R¹ is—CF₂CF₃. In some embodiments, R¹ is

In some embodiments, R⁷ is —H, -halogen, —CN, —NO₂—, —C₁₋₆ aliphatic, or—O—C₁₋₆ aliphatic, wherein each of —C₁₋₆ aliphatic and —O—C₁₋₆ aliphaticis substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂.In some embodiments, R⁷ is unsubstituted —O—C₁₋₆ aliphatic. In someembodiments, R⁷ is —OCH₃. In some embodiments, R⁷ is —O—C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments,R⁷ is —O—C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by-halogen. In some embodiments, R⁷ is —O—C₁₋₆ aliphatic substituted 1, 2,3, 4, 5, or 6 times by —F.

In some embodiments, R⁷ is —H, -halogen, —CN, —NO₂—, or —C₁₋₆ aliphaticsubstituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. Insome embodiments, R⁷ is —H. In some embodiments, R⁷ is -halogen. In someembodiments, R⁷ is —F. In some embodiments, R⁷ is —Cl. In someembodiments, R⁷ is —Br. In some embodiments, R⁷ is —CN. In someembodiments, R⁷ is —NO₂. In some embodiments, R⁷ is unsubstituted —C₁₋₆aliphatic. In some embodiments, R¹ is —CH₃. In some embodiments, R⁷ is—C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen. Insome embodiments, R⁷ is —C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6times by -halogen. In some embodiments, R⁷ is —C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁷ is—C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In someembodiments, R⁷ is —CF₃. In some embodiments, R⁷ is —C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by —CN. In some embodiments, R⁷ is—C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —NO₂.

In some embodiments, R⁷ is phenyl. In some embodiments, R⁷ is —C(CH₃)₃.In some embodiments, R⁷ is —SCF₃. In some embodiments, R⁷ is —S(O)₂CF₃.In some embodiments, R⁷ is —N(CH₃)₂. In some embodiments, R⁷ is —CHF₂.In some embodiments, R⁷ is cyclopropyl. In some embodiments, R⁷ is—CF₂CF₃. In some embodiments, R⁷ is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from the corresponding Ring Amoieties in those compounds depicted in Table 1, below.

As defined generally above, Ring B is an optionally substituted ringselected from phenyl, a 4-, 5-, or 6-membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur,a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4heteroatoms independently selected from nitrogen, oxygen, or sulfur, a8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B is optionally substituted phenyl. In someembodiments, Ring B is optionally substituted 4-, 5-, or 6-memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, Ring B is optionally substituted 4-, 5-, or 6-memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, Ring B is optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring B is optionally substituted 8-10 membered bicyclicaromatic ring. In some embodiments, Ring B is optionally substituted8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring B is an optionally substituted 6-, 7-, 8-, 9-,or 10-membered bicyclic carbocyclic ring. In some embodiments, Ring B isan optionally substituted 6-, 7-, 8-, 9-, or 10-membered bicyclicheterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, Ring Bis an optionally substituted 6-membered bicyclic heterocyclic ringhaving 1 nitrogen.

In some embodiments, Ring B is optionally substituted phenyl or a6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen.

In some embodiments, Ring B is optionally substituted

In some embodiments, Ring B is optionally substituted 1-4 times byhalogen, —S(O)₂N(R)₂—, —S(O)N(R)₂—, —C(O)N(R)₂—, —C(O)OR, —C₁₋₆aliphatic, or —O—C₁₋₆ aliphatic, wherein each of —C₁₋₆ aliphatic and—O—C₁₋₆ aliphatic is independently substituted 0-6 times by halogen,—CN, or —NO₂.

In some embodiments, Ring B is optionally substituted 1-4 times by —F,—Cl, —Br—, —S(O)₂NHCH₃, —S(O)NHCH₃, —C(O)N(CH₃)₂—, —C(O)NHCH₃, —C(O)OH,—C(O)OCH₃, —CH₃, —OCH₃, or —C(CH₃)₃.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is selected from the corresponding Ring Bmoieties in those compounds depicted in Table 1, below.

As defined generally above, R² is —H, or a warhead group.

In some embodiments, R² is —H.

In some embodiments, R² is a warhead group. In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is selected from the corresponding R² moietiesin those compounds depicted in Table 1, below.

As defined generally above, R³ is —H or a warhead group.

In some embodiments, R³ is —H.

In some embodiments, R³ is a warhead group. In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is selected from the corresponding R³ moietiesin those compounds depicted in Table 1, below.

As defined generally above, R⁴ is —H, halogen, —S(O)₂N(R)₂—,—S(O)N(R)₂—, —C(O)N(R)₂—, or a warhead group.

In some embodiments, R⁴ is —H, halogen, —S(O)₂N(R)₂—, —S(O)N(R)₂—,—C(O)N(R)₂—, —C(O)OR, or a warhead group.

In some embodiments, R⁴ is —H.

In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is —F. Insome embodiments, R⁴ is —Cl. In some embodiments, R⁴ is —Br.

In some embodiments, R⁴ is —S(O)₂N(R)₂—, —S(O)N(R)₂—, or —C(O)N(R)₂. Insome embodiments, R⁴ is —S(O)₂N(R)₂. In some embodiments, R⁴ is—S(O)N(R)₂. In some embodiments, R⁴ is —C(O)N(R)₂. In some embodiments,R⁴ is —S(O)₂NHCH₃.

In some embodiments, R⁴ is —S(O)NHCH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃,—C(O)OH, or —C(O)OCH₃.

In some embodiments, R⁴ is a warhead group. In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is selected from the corresponding R⁴ moietiesin those compounds depicted in Table 1, below.

As defined generally above, R⁶ is —H or —C₁₋₆ aliphatic substituted 0,1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂.

In some embodiments, R⁶ is —H, -halogen, —CN, —NO₂—, —C₁₋₆ aliphatic,—OC₁₋₆ aliphatic, or a 4-, 5-, or 6-membered ring having 1, 2, 3, or 4heteroatoms independently selected from nitrogen, oxygen, or sulfuroptionally substituted 1-3 times by —C₁₋₆ aliphatic or —OC₁₋₆ aliphatic,wherein each of —C₁₋₆ aliphatic and —OC₁₋₆ aliphatic is independentlysubstituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂.

In some embodiments, R⁶ is —H. In some embodiments, R⁶ is —F. In someembodiments, R⁶ is —Cl. In some embodiments, R⁶ is —Br. In someembodiments, R⁶ is —CN. In some embodiments, R⁶ is —NO₂.

In some embodiments, R⁶ is —C₁₋₆ aliphatic, substituted 0, 1, 2, 3, 4,5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶ isunsubstituted —C₁₋₆ aliphatic. In some embodiments, R⁶ is —CH₃. In someembodiments, R⁶ is —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 timesby -halogen, —CN, or —NO₂. In some embodiments, R⁶ is —C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R⁶ is—C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In someembodiments, R⁶ is —CF₃.

In some embodiments, R⁶ is —OC₁₋₆ aliphatic, substituted 0, 1, 2, 3, 4,5, or 6 times by -halogen, —CN, or —NO₂. In some embodiments, R⁶ isunsubstituted —OC₁₋₆ aliphatic. In some embodiments, R⁶ is —OCH₃. Insome embodiments, R⁶ is —OC₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6times by -halogen, —CN, or —NO₂. In some embodiments, R⁶ is —OC₁₋₆aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In someembodiments, R⁶ is —OC₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6times by —F. In some embodiments, R⁶ is —OCF₃.

In some embodiments, R⁶ is a 4-, 5-, or 6-membered ring having 1, 2, 3,or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfuroptionally substituted 1-3 times by —C₁₋₆ aliphatic or —OC₁₋₆ aliphatic,wherein each of —C₁₋₆ aliphatic and —OC₁₋₆ aliphatic is independentlysubstituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, —CN, or —NO₂. Insome embodiments, R⁶ is a 5-membered ring having 1, 2, 3, or 4 nitrogenoptionally substituted 1-3 times by —C₁₋₆ aliphatic. In someembodiments, R⁶ is

In some embodiments, R⁶ is selected from the corresponding R⁶ moietiesin those compounds depicted in Table 1, below.

As defined generally above, R^(w) is a warhead group; wherein when R^(w)is a saturated or partially unsaturated monocyclic carbocyclic orheterocyclic ring, it optionally forms a spiro bicyclic ring with RingB.

In some embodiments, R^(w) is a warhead group.

In some embodiments, R^(w) is

In some embodiments, wherein R^(w) is a saturated or partiallyunsaturated monocyclic carbocyclic or heterocyclic ring, R^(w) forms aspiro bicyclic ring with Ring B. In some embodiments, wherein R^(w) is asaturated or partially unsaturated 4-, 5-, or 6-membered carbocyclic orheterocyclic ring, R^(w) forms a spiro bicyclic ring with Ring B. Insome embodiments, wherein R^(w) is optionally substituted

it forms a spiro bicyclic ring with Ring B. In some embodiments, whereinR_(w) is optionally substituted

it forms a spiro bicyclic ring with Ring B, for example

In some embodiments, R^(w) is selected from the corresponding R^(W)moieties in those compounds depicted in Table 1, below.

As defined generally above, R is independently —H or optionallysubstituted —C₁₋₆ aliphatic.

In some embodiments, R is —H.

In some embodiments, R is optionally substituted —C₁₋₆ aliphatic. Insome embodiments, R is unsubstituted —C₁₋₆ aliphatic. In someembodiments, R is —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 timesby -halogen, —CN, or —NO₂. In some embodiments, R is —C₁₋₆ aliphaticsubstituted 1, 2, 3, 4, 5, or 6 times by —F. In some embodiments, R is—C₁₋₃ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by —F. In someembodiments, R is —CF₃.

In some embodiments, R is —CH₃, —C(CH₃)₃, —CHF₂—, cyclopropyl, —CF₂CF₃,or

In some embodiments, R is selected from the corresponding R moieties inthose compounds depicted in Table 1, below.

A “warhead group,” as used herein, is capable of covalently binding toan amino acid residue (such as cysteine, lysine, histidine, or otherresidues capable of being covalently modified) present in the bindingpocket of a target protein, for example, TEAD, thereby irreversiblyinhibiting the protein. In some embodiments, a warhead group is capableof covalently binding to cysteine. In some embodiments, a warhead groupis capable of covalently binding to serine. In some embodiments, awarhead group is capable of covalently binding to lysine. In someembodiments, a warhead group is capable of covalently binding to Cys359of hTEAD1, Cys405 of hTEAD1, Cys380 of hTEAD2, Cys368 of hTEAD3, and/orCys367 of hTEAD4. In some embodiments, a warhead group is capable ofcovalently binding to Ser356 of hTEAD1, Ser345 and/or Ser377 of hTEAD2,Ser365 of hTEAD3, and/or Ser364 of hTEAD4. In some embodiments, awarhead group is capable of covalently binding to Lys336 of hTEAD1,Lys357 of hTEAD2, Lys345 of hTEAD3, and/or Lys344 of hTEAD4.Representative reference amino acid sequences of human TEAD1, humanTEAD2, human TEAD3, and human TEAD4 include UniProt KB ID P28347-1 (SEQID NO: 1), UniProtKB ID Q15562 (SEQ IDNO: 2), UniProtKB ID Q99594 (SEQID NO: 3), and UniProtKB ID Q15561 (SEQ ID NO: 4), respectively. Belowis the sequence alignments of TEAD coactivator binding domains, which isshown in Table 1 of “Targeting Transcriptional Enhanced AssociateDomains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072, the entire contentof which is incorporated herein by reference.

SEQ ID hTEAD1²⁰⁶WQGRSIGTTKLRLNEFSAFLEQQRDPDSYNKHLFVHIGHANHSYSDPLLESNDIRQTYDKFPEKKGGLKE²⁷⁵NO: 5 SEQ ID hTEAD2²¹⁸WQARGLGTARLQLVEFSAFVEPPDAVDSYQRHLFVHISQHCPSPGAPPLESVDVRQIYDKFPEKKGGLRE²⁸⁷NO: 6 SEQ ID hTEAD3²¹⁵WQDRTIASSRLRLLEYSAFMEVQRDPDTYSKHLFVHIGQTNPAFSDPPLEAVDVRQIYDKFPEKKGGLKE²⁸⁴NO: 7 SEQ ID hTEAD4²¹⁴WQGRSVASSKLWMLEFSAFLEQQQDPDTYNKHLFVHIGQSSPSYSDPYLEAVDIRQIYDKFPEKKGGLKD²⁸³NO: 8 SEQ ID hTEAD1²⁷⁶LFGKGPQNAFFLVKFWADLNCNIQ-DDAGA--------FYGVTSQYESSENMTVTCSTKVCSFGKQVVEK³³⁶NO: 5 SEQ ID hTEAD2²⁸⁸LYDRGPPHAFFLVKFWADLNWGPSGEEAGAGGSISSGGFYGVSSQYESLEHMTLTCSSKVCSFGKQVVEK³⁵⁷NO: 6 SEQ ID hTEAD3²⁸⁵LYEKGPPNAFFLVKFWADLNSTIQ-EGPGA--------FYGVSSQYSSADSMTISVSTKVCSFGKQVVEK³⁴⁵NO:7 SEQ ID hTEAD4²⁸⁴LFERGPSNAFFLVKFWADLNTNIE-DEGSS--------FYGVSSQYESPENMIITCSTKVCSFGKQVVEK³⁴⁴NO: 8 SEQ ID hTEAD1³³⁷VETEYARFENGRFVYRINRSPMCEYMINFIFIHKLHLPEKYMMNSVLENFTILLVVTNRDTQETLLCMACV⁴⁰⁶NO: 5 SEQ ID hTEAD2³⁵⁸VETERAQLEDGRFVYRLLRSPMCEYLVNFLHKLRQLPERYMMNSVLENFTILQVVTNRDTQELLLCTAYV⁴²⁷NO: 6 SEQ ID hTEAD3³⁴⁶VETEYARLENGRFVYRIHRSPMCEYMINFIHKLKHLPEKYMMNSVLENFTILQVVTSRDSQETLLVIAFV⁴¹⁵NO: 7 SEQ ID hTEAD4³⁴⁵VETEYARYENGHYSYRIHRSPLCEYMINFIHKLKHLPEKYMMNSVLENFTILQVVTNRDTQETLLCIAYV⁴¹⁴NO: 8 SEQ ID hTEAD1 ⁴⁰⁷FEVSNSEHGAQHHIYRLVKD⁴²⁶ NO: 5 SEQ ID hTEAD2⁴²⁸FEVSTSERGAQHHIYRLVRD⁴⁴⁷ NO: 6 SEQ ID hTEAD3⁴¹⁶FEVSTSEHGAQHHVYKLVKD⁴³⁵ NO: 7 SEQ ID hTEAD4⁴¹⁵FEVSASEHGAQHHIYRLVKE⁴³⁴ NO: 8

In some embodiments, a warhead group is -L-Y, wherein:

-   L is a covalent bond or a bivalent C₁₋₈ saturated or unsaturated,    straight or branched, hydrocarbon chain, wherein one, two, or three    methylene units of L are optionally and independently replaced by    cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR)—,    —N═N—, or —C(═N₂)—;-   Y is hydrogen, C₁₋₆ aliphatic optionally substituted with oxo,    halogen, NO₂—, or CN, or a 3-10 membered monocyclic or bicyclic,    saturated, partially unsaturated, or aryl ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    and wherein said ring is substituted with 1-4 R^(e) groups; and    each R^(e) is independently selected from -Q-Z, oxo, NO₂—, halogen,    CN, a suitable leaving group, or    -   a C₁₋₆ aliphatic optionally substituted with oxo, halogen, NO₂—,        or CN, wherein:        -   Q is a covalent bond or a bivalent C₁₋₆ saturated or            unsaturated, straight or branched, hydrocarbon chain,            wherein one or two methylene units of Q are optionally and            independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—,            —C(O)O—, —SO—, or —SO₂—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—,            or —SO₂N(R)—; and        -   Z is hydrogen or C₁₋₆ aliphatic optionally substituted with            oxo, halogen, NO₂—, or CN.

In certain embodiments, L is a covalent bond.

In certain embodiments, L is a bivalent C₁₋₈ saturated or unsaturated,straight or branched, hydrocarbon chain. In certain embodiments, L is—CH₂—.

In certain embodiments, L is a covalent bond, —CH₂—, —NH—, —CH₂NH—,—NHCH₂—, —NHC(O)—, —NHC(O)CH₂OC(O)—, —CH₂NHC(O)—, —NHSO₂—, —NHSO₂CH₂—,—NHC(O)CH₂OC(O)—, or —SO₂NH—.

In some embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one double bond and one or twoadditional methylene units of L are optionally and independentlyreplaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—,—SO₂—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—.

In certain embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one double bond and at leastone methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—,—N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and oneor two additional methylene units of L are optionally and independentlyreplaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

In some embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one double bond and at leastone methylene unit of L is replaced by —C(O)—, and one or two additionalmethylene units of L are optionally and independently replaced bycyclopropylene, —O—, —N(R)—, or —C(O)—.

As described above, in certain embodiments, L is a bivalent C₂₋₈straight or branched, hydrocarbon chain wherein L has at least onedouble bond. One of ordinary skill in the art will recognize that such adouble bond may exist within the hydrocarbon chain backbone or may be“exo” to the backbone chain and thus forming an alkylidene group. By wayof example, such an L group having an alkylidene branched chain includes—CH₂C(═CH₂)CH₂—. Thus, in some embodiments, L is a bivalent C₂₋₈straight or branched, hydrocarbon chain wherein L has at least onealkylidenyl double bond. Exemplary L groups include —NHC(O)C(═CH₂)CH₂—.

In certain embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one double bond and at leastone methylene unit of L is replaced by —C(O)—. In certain embodiments, Lis —C(O)CH═CH(CH₃)—, —C(O)CH═CHCH₂NH(CH₃)—, —C(O)CH═CH(CH₃)—,—C(O)CH═CH—, —CH₂C(O)CH═CH—, —CH₂C(O)CH═CH(CH₃)—, —CH₂CH₂C(O)CH═CH—,—CH₂CH₂C(O)CH═CHCH₂—, —CH₂CH₂C(O)CH═CHCH₂NH(CH₃)—, or—CH₂CH₂C(O)CH═CH(CH₃)—, or —CH(CH₃)OC(O)CH═CH—.

In certain embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one double bond and at leastone methylene unit of L is replaced by —OC(O).

In some embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one double bond and at leastone methylene unit of L is replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—,—SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or twoadditional methylene units of L are optionally and independentlyreplaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. In some embodiments,L is —CH₂OC(O)CH═CHCH₂—, —CH₂—OC(O)CH═CH—, or —CH(CH═CH₂)OC(O)CH═CH—.

In certain embodiments, L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH₂N(CH₃)—,—NRC(O)CH═CHCH₂O—, —CH₂NRC(O)CH═CH—, —NRSO₂CH═CH—, —NRSO₂CH═CHCH₂—,—NRC(O)(C═N₂)C(O)—, —NRC(O)CH═CHCH₂N(CH₃)—, —NRSO₂CH═CH—,—NRSO₂CH═CHCH₂—, —NRC(O)CH═CHCH₂O—, —NRC(O)C(═CH₂)CH₂—, —CH₂NRC(O)—,—CH₂NRC(O)CH═CH—, —CH₂CH₂NRC(O)—, or —CH₂NRC(O)cyclopropylene-, whereineach R is independently hydrogen or optionally substituted C₁₋₆aliphatic.

In certain embodiments, L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH₂N(CH₃)—,—NHC(O)CH═CHCH₂O—, —CH₂NHC(O)CH═CH—, —NHSO₂CH═CH—, —NHSO₂CH═CHCH₂—,—NHC(O)(C═N₂)C(O)—, —NHC(O)CH═CHCH₂N(CH₃)—, —NHSO₂CH═CH—,—NHSO₂CH═CHCH₂—, —NHC(O)CH═CHCH₂O—, NHC(O)C(═CH₂)CH₂—, —CH₂NHC(O)—,—CH₂NHC(O)CH═CH—, —CH₂CH₂NHC(O)—, or —CH₂NHC(O)cyclopropylene-.

In some embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein L has at least one triple bond. In certainembodiments, L is a bivalent C₂₋₈ straight or branched, hydrocarbonchain wherein L has at least one triple bond and one or two additionalmethylene units of L are optionally and independently replaced by—NRC(O)—, —C(O)NR—, —S—, —S(O)—, —SO₂—, —C(═S)—, —C(═NR)—, —O—, —N(R)—,or —C(O)—. In some embodiments, L has at least one triple bond and atleast one methylene unit of L is replaced by —N(R)—, —N(R)C(O)—, —C(O)—,—C(O)O—, or OC(O)—, or —O—.

Exemplary L groups include —C≡C—, —C≡CCH₂N(isopropyl)-,—NHC(O)C≡CCH₂CH₂—, —CH₂—C≡C≡CH₂—, C≡CCH₂O—, —CH₂C(O)C≡C—, —C(O)C≡C—, or—CH₂OC(═O)C≡C—.

In certain embodiments, L is a bivalent C₂₋₈ straight or branched,hydrocarbon chain wherein one methylene unit of L is replaced bycyclopropylene and one or two additional methylene units of L areindependently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—, or—SO₂N(R)—. Exemplary L groups include —NHC(O)-cyclopropylene-SO₂— and—NHC(O)-cyclopropylene-.

As defined generally above, Y is hydrogen, C₁₋₆ aliphatic optionallysubstituted with oxo, halogen, NO₂—, or CN, or a 3-10 memberedmonocyclic or bicyclic, saturated, partially unsaturated, or aryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, and wherein said ring is substituted with at 1-4 R^(e) groups,each R^(e) is independently selected from -Q-Z, oxo, NO₂—, halogen, CN,a suitable leaving group, or C₁₋₆ aliphatic, wherein Q is a covalentbond or a bivalent C₁₋₆ saturated or unsaturated, straight or branched,hydrocarbon chain, wherein one or two methylene units of Q areoptionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—,OC(O)—, —C(O)O, —SO—, or SO₂—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, or—SO₂N(R)—; and, Z is hydrogen or C₁₋₆ aliphatic optionally substitutedwith oxo, halogen, NO₂—, or CN.

In certain embodiments, Y is hydrogen.

In certain embodiments, Y is C₁₋₆ aliphatic optionally substituted withoxo, halogen, NO₂—, or CN. In some embodiments, Y is C₂₋₆alkenyloptionally substituted with oxo, halogen, NO₂—, or CN. In otherembodiments, Y is C₂₋₆alkynyl optionally substituted with oxo, halogen,NO₂—, or CN. In some embodiments, Y is C₂₋₆alkenyl. In otherembodiments, Y is C₂₋₄ alkynyl.

In other embodiments, Y is C₁₋₆ alkyl substituted with oxo, halogen,NO₂—, or CN. Such Y groups include —CH₂F, —CH₂Cl, —CH₂CN, and —CH₂NO₂.

In certain embodiments, Y is a saturated 3-6 membered monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein Y is substituted with 1-4 R^(e) groups, wherein eachR^(e) is as defined above and described herein.

In some embodiments, Y is a saturated 3-4 membered heterocyclic ringhaving 1 heteroatom selected from oxygen or nitrogen wherein said ringis substituted with 1-2 R^(e) groups, wherein each R^(e) is as definedabove and described herein. Exemplary such rings are epoxide and oxetanerings, wherein each ring is substituted with 1-2 R^(e) groups, whereineach R^(e) is as defined above and described herein.

In other embodiments, Y is a saturated 5-6 membered heterocyclic ringhaving 1-2 heteroatom selected from oxygen or nitrogen wherein said ringis substituted with 1-4 R^(e) groups, wherein each R^(e) is as definedabove and described herein. Such rings include piperidine andpyrrolidine, wherein each ring is substituted with 1-4 R^(e) groups,wherein each R^(e) is as defined above and described herein. In certainembodiments, Y is

wherein each R, Q, Z, and R^(e) is as defined above and describedherein.

In some embodiments, Y is a saturated 3-6 membered carbocyclic ring,wherein said ring is substituted with 1-4 R^(e) groups, wherein eachR^(e) is as defined above and described herein. In certain embodiments,Y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein eachring is substituted with 1-4 R^(e) groups, wherein each R^(e) is asdefined above and described herein. In certain embodiments, Y is

wherein R^(e) is as defined above and described herein.

In certain embodiments, Y is cyclopropyl optionally substituted withhalogen, CN or NO₂.

In certain embodiments, Y is a partially unsaturated 3-6 memberedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4R^(e) groups, wherein each R^(e) is as defined above and describedherein.

In some embodiments, Y is a partially unsaturated 3-6 memberedcarbocyclic ring, wherein said ring is substituted with 1-4 R^(e)groups, wherein each R^(e) is as defined above and described herein. Insome embodiments, Y is cyclopropenyl, cyclobutenyl, cyclopentenyl, orcyclohexenyl wherein each ring is substituted with 1-4 R^(e) groups,wherein each R^(e) is as defined 0-3 above and described herein. Incertain embodiments, Y is

wherein each R^(e) is as defined above and described herein.

In certain embodiments, Y is a partially unsaturated 4-6 memberedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4R^(e) groups, wherein each R^(e) is as defined above and describedherein. In certain embodiments, Y is selected from:

wherein each R and R^(e) is as defined above and described herein.

In certain embodiments, Y is a 6-membered aromatic ring having 0-2nitrogens wherein said ring is substituted with 1-4 R^(e) groups,wherein each R^(e) group is as defined above and described herein. Incertain embodiments, Y is phenyl, pyridyl, or pyrimidinyl, wherein eachring is substituted with 1-4 R^(e) groups, wherein each R^(e) is asdefined above and described herein.

In some embodiments, Y is selected from:

wherein each R^(e) is as defined above and described herein.

In other embodiments, Y is a 5-membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein said ring is substituted with 1-3 R^(e) groups, wherein eachR^(e) group is as defined above and described herein. In someembodiments, Y is a 5 membered partially unsaturated or aryl ring having1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein said ring is substituted with 1-4 R^(e) groups, whereineach R^(e) group is as defined above and described herein. Exemplarysuch rings are isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,pyrrolyl, furanyl, thienyl, triazole, thiadiazole, and oxadiazole,wherein each ring is substituted with 1-3 R^(e) groups, wherein eachRegroup is as defined above and described herein. In certainembodiments, Y is selected from:

wherein each R and R^(e) is as defined above and described herein.

In certain embodiments, Y is an 8-10 membered bicyclic, saturated,partially unsaturated, or aryl ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein said ring issubstituted with 1-4 R^(e) groups, wherein R^(e) is as defined above anddescribed herein. According to another aspect, Y is a 9-10 memberedbicyclic, partially unsaturated, or aryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein saidring is substituted with 1-4 R^(e) groups, wherein R^(e) is as definedabove and described herein. Exemplary such bicyclic rings include2,3-dihydrobenzo[d]isothiazole, wherein said ring is substituted with1-4 R^(e) groups, wherein R^(e) is as defined above and describedherein.

As defined generally above, each R^(e) group is independently selectedfrom -Q-Z, oxo, NO₂—, halogen, CN, a suitable leaving group, or C₁₋₆aliphatic optionally substituted with oxo, halogen, NO₂—, or CN, whereinQ is a covalent bond or a bivalent C₁₋₆ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one or two methyleneunits of Q are optionally and independently replaced by —N(R)—, —S—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO₂—, —N(R)C(O)—, —C(O)N(R)—,—N(R)SO₂—, or —SO₂N(R)—; and Z is hydrogen or C₁₋₆ aliphatic optionallysubstituted with oxo, halogen, NO₂—, or CN.

In certain embodiments, R^(e) is C₁₋₆ aliphatic optionally substitutedwith oxo, halogen, NO₂—, or CN. In other embodiments, R^(e) is oxo,NO₂—, halogen, or CN.

In some embodiments, R^(e) is -Q-Z, wherein Q is a covalent bond and Zis hydrogen (i.e., R^(e) is hydrogen). In other embodiments, R^(e) is-Q-Z, wherein Q is a bivalent C₁₋₆ saturated or unsaturated, straight orbranched, hydrocarbon chain, wherein one or two methylene units of Q areoptionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—,—O—, —C(O)—, —SO—, or —SO₂—. In other embodiments, Q is a bivalent C₂₋₆straight or branched, hydrocarbon chain having at least one double bond,wherein one or two methylene units of Q are optionally and independentlyreplaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO₂—.In certain embodiments, the Z moiety of the R^(e) group is hydrogen. Insome embodiments, -Q-Z is —NHC(O)CH═CH₂ or —C(O)CH═CH₂.

In certain embodiments, each R^(e) is independently selected from oxo,NO₂—, CN, fluoro, chloro, —NHC(O)CH═CH₂—, —C(O)CH═CH₂—, —CH₂CH═CH₂—,—C≡CH, —C(O)OCH₂Cl, —C(O)OCH₂F, —C(O)OCH₂CN, —C(O)CH₂Cl, —C(O)CH₂F,—C(O)CH₂CN, or —CH₂C(O)CH₃.

In certain embodiments, R^(e) is a suitable leaving group, ie a groupthat is subject to nucleophilic displacement. A “suitable leaving” is achemical group that is readily displaced by a desired incoming chemicalmoiety such as the thiol moiety of a cysteine of interest. Suitableleaving groups are well known in the art, e.g., see, “Advanced OrganicChemistry,” Jerry March, 5^(th) Ed., pp. 351-357, John Wiley and Sons,N.Y. Such leaving groups include, but are not limited to, halogen,alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy,optionally substituted alkenylsulfonyloxy, optionally substitutedarylsulfonyloxy, acyl, and diazonium moieties. Examples of suitableleaving groups include chloro, iodo, bromo, fluoro, acetoxy,methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy,nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy(brosyloxy).

In certain embodiments, the following embodiments and combinations of-L-Y apply:

-   (a) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one double bond and one or two additional    methylene units of L are optionally and independently replaced by    —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—,    —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is    hydrogen or C₁₋₆ aliphatic optionally substituted with oxo, halogen,    NO₂, or CN; or-   (b) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one double bond and at least one methylene    unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO₂—,    —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and one or two    additional methylene units of L are optionally and independently    replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is    hydrogen or C₁₋₆ aliphatic optionally substituted with oxo, halogen,    NO₂, or CN; or-   (c) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one double bond and at least one methylene    unit of L is replaced by —C(O)—, and one or two additional methylene    units of L are optionally and independently replaced by    cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C₁₋₆    aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or-   (d) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one double bond and at least one methylene    unit of L is replaced by —C(O)—; and Y is hydrogen or C₁₋₆ aliphatic    optionally substituted with oxo, halogen, NO₂, or CN; or-   (e) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one double bond and at least one methylene    unit of L is replaced by —OC(O)—; and Y is hydrogen or C₁₋₆    aliphatic optionally substituted with oxo, halogen, NO₂, or CN; or-   (f) L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH₂N(CH₃)—, —NRC(O)CH═CHCH₂O—,    —CH₂NRC(O)CH═CH—, —NRSO₂CH═CH—, —NRSO₂CH═CHCH₂—, —NRC(O)(C═N₂)—,    —NRC(O)(C═N₂)C(O)—, —NRC(O)CH═CHCH₂N(CH₃)—, —NRSO₂CH═CH—,    —NRSO₂CH═CHCH₂—, —NRC(O)CH═CHCH₂O—, —NRC(O)C(═CH₂)CH₂—, —CH₂NRC(O)—,    —CH₂NRC(O)CH═CH—, —CH₂CH₂NRC(O)—, or —CH₂NRC(O)cyclopropylene-;    wherein R is H or optionally substituted C₁₋₆ aliphatic; and Y is    hydrogen or C₁₋₆ aliphatic optionally substituted with oxo, halogen,    NO₂, or CN; or-   (g) L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH₂N(CH₃)—, —NHC(O)CH═CHCH₂O—,    —CH₂NHC(O)CH═CH—, —NHSO₂CH═CH—, NHSO₂CH═CHCH₂—, —NHC(O)(C═N₂)—,    —NHC(O)(C═N₂)C(O)—, —NHC(O)CH═CHCH₂N(CH₃)—, —NHSO₂CH═CH—,    —NHSO₂CH═CHCH₂—, —NHC(O)CH═CHCH₂O—, —NHC(O)C(═CH₂)CH₂—, —CH₂NHC(O)—,    —CH₂NHC(O)CH═CH—, —CH₂CH₂NHC(O)—, or —CH₂NHC(O)cyclopropylene-; and    Y is hydrogen or C₁₋₆ aliphatic optionally substituted with oxo,    halogen, NO₂, or CN; or-   (h) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one alkylidenyl double bond and at least one    methylene unit of L is replaced by C(O)—, —NRC(O)—, —C(O)NR—,    —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—, —OC(O)—, or —C(O)O—, and    one or two additional methylene units of L are optionally and    independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;    and Y is hydrogen or C₁₋₆ aliphatic optionally substituted with oxo,    halogen, NO₂, or CN; or-   (i) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein L has at least one triple bond and one or two additional    methylene units of L are optionally and independently replaced by    —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—, —SO₂—,    —OC(O)—, or —C(O)O—, and Y is hydrogen or C₁₋₆ aliphatic optionally    substituted with oxo, halogen, NO₂, or CN; or-   (j) L is —C≡C—, —C≡CCH₂N(isopropyl)-, —NHC(O)C≡CCH₂CH₂—,    —CH₂—C≡C≡CH₂—, —C≡CCH₂O—, —CH₂C(O)C≡C—, —C(O)C≡C—, or —CH₂C(═O)C≡C—;    and Y is hydrogen or C₁₋₆ aliphatic optionally substituted with oxo,    halogen, NO₂, or CN; or-   (k) L is a bivalent C₂₋₈ straight or branched, hydrocarbon chain    wherein one methylene unit of L is replaced by cyclopropylene and    one or two additional methylene units of L are independently    replaced by —NRC(O)—, —C(O)NR—, —N(R)SO₂—, —SO₂N(R)—, —S—, —S(O)—,    —SO₂—, —OC(O)—, or —C(O)O—; and Y is hydrogen or C₁₋₆ aliphatic    optionally substituted with oxo, halogen, NO₂, or CN; or-   (l) L is a covalent bond and Y is selected from:    -   (i) C₁₋₆ alkyl substituted with oxo, halogen, NO₂, or CN;    -   (ii) C₂₋₆alkenyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iii) C₂₋₆alkynyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iv) a saturated 3-4 membered heterocyclic ring having 1        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-2 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (v) a saturated 5-6 membered heterocyclic ring having 1-2        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-4 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (vi)

-   -    wherein each R, Q, Z, and R^(e) is as defined above and        described herein; or    -   (vii) a saturated 3-6 membered carbocyclic ring, wherein said        ring is substituted with 1-4 R^(e) groups, wherein each R^(e) is        as defined above and described herein; or    -   (viii) a partially unsaturated 3-6 membered monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (ix) a partially unsaturated 3-6 membered carbocyclic ring,        wherein said ring is substituted with 1-4 R^(e) groups, wherein        each R^(e) is as defined above and described herein; or    -   (x)

-   -    wherein each R^(e) is as defined above and described herein; or    -   (xi) a partially unsaturated 4-6 membered heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (xii)

-   -    wherein each R and R^(e) is as defined above and described        herein; or    -   (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein        said ring is substituted with 1-4 R^(e) groups, wherein each R        group is as defined above and described herein; or    -   (xiv)

-   -    wherein each R is as defined above and described herein; or    -   (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        said ring is substituted with 1-3 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or    -   (xvi)

-   -   wherein each R and R^(e) is as defined above and described        herein; or    -   (xvii) an 8-10 membered bicyclic, saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, wherein said ring is        substituted with 1-4 R^(e) groups, wherein R^(e) is as defined        above and described herein;

-   (m) L is —C(O)— and Y is selected from.    -   (i) C¹⁻⁶ alkyl substituted with oxo, halogen, NO², or CN; or    -   (ii) C₂₋₆alkenyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iii) C₂₋₆alkynyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iv) a saturated 3-4 membered heterocyclic ring having 1        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-2 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (v) a saturated 5-6 membered heterocyclic ring having 1-2        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-4 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (vi)

-   -    wherein each R, Q, Z, and R^(e) is as defined above and        described herein; or    -   (vii) a saturated 3-6 membered carbocyclic ring, wherein said        ring is substituted with 1-4 R^(e) groups, wherein each R^(e) is        as defined above and described herein; or    -   (viii) a partially unsaturated 3-6 membered monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (ix) a partially unsaturated 3-6 membered carbocyclic ring,        wherein said ring is substituted with 1-4 R^(e) groups, wherein        each R^(e) is as defined above and described herein; or    -   (x)

-   -    wherein each R^(e) is as defined above and described herein; or    -   (xi) a partially unsaturated 4-6 membered heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (xii)

-   -   wherein each R and R^(e) is as defined above and described        herein; or    -   (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein        said ring is substituted with 1-4 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or    -   (xiv)

-   -   wherein each R^(e) is as defined above and described herein; or    -   (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        said ring is substituted with 1-3 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or

-   -   wherein each R and R^(e) is as defined above and described        herein; or    -   (xvii) an 8-10 membered bicyclic, saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, wherein said ring is        substituted with 1-4 R^(e) groups, wherein R^(e) is as defined        above and described herein;

-   (n) L is N(R)C(O) and Y is selected from:    -   (i) C₁₋₆ alkyl substituted with oxo, halogen, NO₂, or CN; or    -   (ii) C₂₋₆alkenyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iii) C₂₋₆alkynyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iv) a saturated 3-4 membered heterocyclic ring having 1        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-2 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (v) a saturated 5-6 membered heterocyclic ring having 1-2        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-4 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (vi)

-   -    wherein each R, Q, Z, and R^(e) is as defined above and        described herein; or    -   (vii) a saturated 3-6 membered carbocyclic ring, wherein said        ring is substituted with 1-4 R^(e) groups, wherein each R^(e) is        as defined above and described herein; or    -   (viii) a partially unsaturated 3-6 membered monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (ix) a partially unsaturated 3-6 membered carbocyclic ring,        wherein said ring is substituted with 1-4 R^(e) groups, wherein        each R^(e) is as defined above and described herein; or    -   (x)

-   -    wherein each R^(e) is as defined above and described herein; or    -   (xi) a partially unsaturated 4-6 membered heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (xii)

-   -    wherein each R and R^(e) is as defined above and described        herein; or    -   (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein        said ring is substituted with 1-4 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or    -   (xiv)

-   -    wherein each R is as defined above and described herein; or    -   (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        said ring is substituted with 1-3 R^(e) groups, wherein each R        group is as defined above and described herein; or

-   -   wherein each R and R is as defined above and described herein;        or    -   (xvii) an 8-10 membered bicyclic, saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, wherein said ring is        substituted with 1-4 R^(e) groups, wherein R^(e) is as defined        above and described herein;

-   (o) L is a bivalent C₁₋₈ saturated or unsaturated, straight or    branched, hydrocarbon chain; and Y is selected from:    -   (i) C₁₋₆ alkyl substituted with oxo, halogen, NO₂, or CN;    -   (ii) C₂₋₆alkenyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iii) C₂₋₆alkynyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iv) a saturated 3-4 membered heterocyclic ring having 1        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-2 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (v) a saturated 5-6 membered heterocyclic ring having 1-2        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-4 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (vi)

-   -    wherein each R, Q, Z, and R^(e) is as defined above and        described herein; or    -   (vii) a saturated 3-6 membered carbocyclic ring, wherein said        ring is substituted with 1-4 R^(e) groups, wherein each R^(e) is        as defined above and described herein; or    -   (viii) a partially unsaturated 3-6 membered monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (ix) a partially unsaturated 3-6 membered carbocyclic ring,        wherein said ring is substituted with 1-4 R^(e) groups, wherein        each R^(e) is as defined above and described herein; or    -   (x)

-   -    wherein each R^(e) is as defined above and described herein; or    -   (xi) a partially unsaturated 4-6 membered heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (xii)

-   -    wherein each R and R^(e) is as defined above and described        herein; or    -   (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein        said ring is substituted with 1-4 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or    -   (xiv)

-   -    wherein each R is as defined above and described herein; or    -   (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        said ring is substituted with 1-3 R^(e) groups, wherein each R        group is as defined above and described herein; or

-   -   wherein each R and R is as defined above and described herein;        or    -   (xvii) an 8-10 membered bicyclic, saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, wherein said ring is        substituted with 1-4 R^(e) groups, wherein R^(e) is as defined        above and described herein;

-   (p) L is a covalent bond, —CH₂—, —NH—, —C(O)—, —CH₂NH—, —NHCH₂—,    —NHC(O)—, —NHC(O)CH₂OC(O)—, —CH₂NHC(O)—, —NHSO₂—, —NHSO₂CH₂—,    —NHC(O)CH₂OC(O)—, or —SO₂NH—; and Y is selected from:    -   (i) C₁₋₆ alkyl substituted with oxo, halogen, NO₂, or CN; or    -   (ii) C₂₋₆alkenyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iii) C₂₋₆alkynyl optionally substituted with oxo, halogen, NO₂,        or CN; or    -   (iv) a saturated 3-4 membered heterocyclic ring having 1        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-2 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (v) a saturated 5-6 membered heterocyclic ring having 1-2        heteroatom selected from oxygen or nitrogen wherein said ring is        substituted with 1-4 R^(e) groups, wherein each R^(e) is as        defined above and described herein; or    -   (vi)

-   -    wherein each R, Q, Z, and R^(e) is as defined above and        described herein; or    -   (vii) a saturated 3-6 membered carbocyclic ring, wherein said        ring is substituted with 1-4 R^(e) groups, wherein each R^(e) is        as defined above and described herein; or    -   (viii) a partially unsaturated 3-6 membered monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (ix) a partially unsaturated 3-6 membered carbocyclic ring,        wherein said ring is substituted with 1-4 R^(e) groups, wherein        each R^(e) is as defined above and described herein; or    -   (x)

-   -    wherein each R^(e) is as defined above and described herein; or    -   (xi) a partially unsaturated 4-6 membered heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein said ring is substituted with 1-4        R^(e) groups, wherein each R^(e) is as defined above and        described herein; or    -   (xii)

-   -    wherein each R and R^(e) is as defined above and described        herein; or    -   (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein        said ring is substituted with 1-4 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or    -   (xiv)

-   -   wherein each R^(e) is as defined above and described herein; or    -   (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        said ring is substituted with 1-3 R^(e) groups, wherein each        R^(e) group is as defined above and described herein; or

-   -   wherein each R and R^(e) is as defined above and described        herein; or    -   (xvii) an 8-10 membered bicyclic, saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, wherein said ring is        substituted with 1-4 R^(e) groups, wherein R^(e) is as defined        above and described herein.

In certain embodiments, the Y group is selected from those set forth inTable 1-1 below, wherein each wavy line indicates the point ofattachment to the rest of the molecule.

TABLE 1-1 Exemplary Y groups

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

ss

tt

uu

vv

ww

xx

yy

zz

aaa

bbb

ccc

ddd

eee

fff

ggg

hhh

iii

jjj

kkk

lll

mmm

nnn

ooo

ppp

qqq

rrr

sss

ttt

uuu

vvv

qqq

www

xxx

yyy

zzz

aaaa

bbbb

cccc

dddd

eeee

ffff

gggg

hhhh

iiii

jjjj

kkkk

llll

mmmm

nnnn

oooo

pppp

qqqq

rrrr

ssss

tttt

uuuu

vvvv

wwww

xxxx

yyyy

zzzz

aaaaa

bbbbb

cccccwherein each R^(e) is independently a suitable leaving group, NO₂—, CNor oxo.

In certain embodiments, a warhead group is —C≡CH, —C≡CCH₂NH(isopropyl),—NHC(O)C≡CCH₂CH₃, —CH₂—C≡C≡CH₃, —C≡CCH₂OH, —CH₂C(O)C≡CH, —C(O)C≡CH, or—CH₂C(═O)C≡CH—. In some embodiments, R¹ is selected from —NHC(O)CH═CH₂,—NHC(O)CH═CHCH₂N(CH₃)₂, or —CH₂NHC(O)CH═CH₂.

In certain embodiments, a warhead group is selected from those set forthin Table 1-2, below, wherein each wavy line indicates the point ofattachment to the rest of the molecule.

TABLE 1-2 Exemplary Warhead Groups

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

ss

tt

uu

vv

ww

xx

yy

zz

aaa

bbb

ccc

ddd

eee

fff

ggg

hhh

iii

jjj

kkk

lll

mmm

nnn

ooo

ppp

qqq

rrr

sss

ttt

uuu

vvv

www

xxx

yyy

zzz

aaaa

bbbb

cccc

dddd

eeee

ffff

gggg

hhhh

iiii

jjjj

kkkk

llll

mmmm

nnnn

oooo

pppp

qqqq

rrrr

ssss

tttt

uuuu

vvvv

wwww

xxxx

yyyy

zzzz

aaaaa

bbbbb

ccccc

ddddd

eeeee

fffff

ggggg

hhhhh

iiiii

jjjjj

kkkkk

lllll

mmmmm

nnnnn

ooooo

ppppp

qqqqq

rrrrr

sssss

ttttt

uuuuu

vvvvv

wwwww

xxxxx

yyyyy

zzzzz

aaaaaa

bbbbbb

cccccc

dddddd

eeeeee

ffffff

gggggg

hhhhhh

iiiiii

jjjjjj

kkkkkk

llllll

mmmmmm

nnnnnn

oooooo

pppppp

qqqqqq

rrrrrr

ssssss

tttttt

uuuuuu

vvvvvv

wwwwww or

xxxxxxwherein each R^(e) is independently a suitable leaving group, NO₂—, CN,or oxo.

In some embodiments, Y of a warhead group is an isoxazoline compound orderivative capable of covalently binding to serine. In some embodiments,Y of a warhead group is an isoxazoline compound or derivative describedin WO 2010135360, the entire content of which is incorporated herein byreference. As understood by one skilled in the art, an isoxazolinecompound or derivative described in WO 2010135360, as Y of a warheadgroup, can covalently connect to L of the warhead group at anyreasonable position of the isoxazoline compound or derivative. In someembodiments, Y of a warhead group is:

wherein G, R^(a), and R^(c) are:

G R^(a) R^(c) —Br —H —H —Cl —H —H

—H —H

—H —B

—B —H

—B —H

—H —H

—H —B

—H —H

—B —H

—B —H

—H —H

—H —H

—N —B

—N —H

—H —B

—H —H

—H —H

—H —B

—H —B

—H —B

—H —B

—H —B —OMe —H —H

—H —H

—H —H

—H —H

—H —H

—B —B

—B —B

—H —H

—B —B

—B —B

—B —H

—H —H

—H —H

—H —H

—H —H

—H —H

—H —H

—H —H

—B —H

—H —H

—B —H

—H —H

—H —B

—H —H

—H —B

—H —H

—B —H

—H —H

—B —H

—B —B

—H —H

—N —B

—H —H

—H —H

—B —B

—B —B

—H —H —Br —CH₃ —B —Br —CH₃ —H

—CH₃ —H —Br —H —CH₃

—N —CH₃ —Br —H —CF₃

—H —CF₃ —Br —B —CH₂CH₃

In some embodiments, the present invention provides a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein the variables areas described herein.

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —NH—;-   R¹ is —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by    halogen;-   R² is a warhead group;-   R³ is —H;-   R⁴ is —H, —S(O)₂N(R)₂; —S(O)N(R)₂, or —C(O)N(R)₂, each R    independently is selected from —H and optionally substituted —C₁₋₆    aliphatic;-   R⁶ is —H or —C₁₋₆ aliphatic; and-   R⁷ is —H,    with the proviso that the compound is not

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —NH—;-   R¹ is —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by    halogen;-   R² is an optionally substituted 5-membered aromatic ring having 1,    2, 3, or 4 nitrogen;-   R³ is —H;-   R⁴ is a warhead group;-   R⁶ is —H or —C₁₋₆ aliphatic; and-   R⁷ is —H.

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —O—;-   R¹ is —H, or —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times    by halogen;-   R² is —H;-   R³ is a warhead group;-   R⁴ is —H;-   R⁶ is —H or —C₁₋₆ aliphatic;-   R⁷ is —H.

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —O—;-   R¹ is —H, or —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times    by halogen;-   R² is —H;-   R³ is a warhead group;-   R⁴ is —H;-   R⁶ is —H;-   R⁷ is —H or halogen.

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —O—;-   R¹ is —H, or —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times    by halogen;-   R² is —H;-   R³ is a warhead group;-   R⁴ is —H;-   R⁶ is —H or —C₁₋₆ aliphatic; and-   R⁷ is —H or halogen,    with the proviso that the compound is not

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —NH—;-   R¹ is —H, or —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times    by halogen;-   R² is —H;-   R³ is a warhead group;-   R⁴ is —H;-   R⁶ is —H or —C₁₋₆ aliphatic;-   R⁷ is —H or halogen.

In some embodiments, the present invention provides a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —NH—;-   R¹ is —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by    halogen;-   each of R² and R⁴ independently is a warhead group;-   R³ is —H;-   R⁶ is —H or —C₁₋₆ aliphatic; and-   R⁷ is —H or halogen.

In some embodiments, the present invention provides a compound ofFormula III:

or a pharmaceutically acceptable salt thereof, wherein the variables areas described herein.

In some embodiments, the present invention provides a compound ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein:

-   L¹ is —NH—;-   R¹ is —C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by    halogen;-   R² is a warhead group;-   R³ is —H;-   R⁴ is —S(O)₂N(R)₂—, —S(O)N(R)₂—, or —C(O)N(R)₂—, each R    independently is selected from —H and optionally substituted —C₁₋₆    aliphatic;-   R⁶ is —H or —C₁₋₆ aliphatic; and-   R⁷ is —H or halogen,    with the proviso that the compound is not

In some embodiments, the present invention provides a compound ofFormula (IV):

or a pharmaceutically acceptable salt thereof, wherein each of X isindependently C or N; and each of Ring A, R^(w), and L¹ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound ofFormula (IVa) or (IVb):

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R⁷,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula (V):

or a pharmaceutically acceptable salt thereof, wherein each of X isindependently C or N; and each of Ring A, R^(w), and L¹ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound ofFormula (Va) or (Vb):

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R⁷,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula (VI):

or a pharmaceutically acceptable salt thereof, wherein each of X isindependently C or N; and each of Ring A, R^(w), and L¹ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound ofFormula (VIa) or (VIb):

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R⁷,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula (VII):

or a pharmaceutically acceptable salt thereof, wherein each of X isindependently C or N; and each of Ring A, R^(w), and L¹ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound ofFormula (VIIa) or (VIIb):

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R⁷,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula (VIII):

or a pharmaceutically acceptable salt thereof, wherein each of X isindependently C or N; and each of Ring A, R^(w), and L¹ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound ofFormula (VIIIa) or (VIIIb):

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R⁷,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormulas (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (VIa), (VIb), (VII),(VIIa), (VIIb), (VIII), (VIIIa), or (VIIIb), or a pharmaceuticallyacceptable salt thereof, wherein L¹ is —CH₂—, —O—, —CH(CH₃)—, —NH—,—C(O)—, or —NH—CH₂—; R¹ is —H or —C₁₋₆ aliphatic substituted 1, 2, 3, 4,5, or 6 times by halogen; R^(w) is a warhead group; and R⁷ is —H or—C₁₋₆ aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen.

In some embodiments, the present invention provides a compound ofFormula (I′), or a pharmaceutically acceptable salt thereof, whereinRing A is phenyl, a 6-membered monocyclic heteroaromatic ring having 1or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2nitrogen; Ring B is phenyl or a 6-membered monocyclic heteroaromaticring having 1 or 2 nitrogen; and each of R^(w) and L¹ is as definedabove and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound ofFormula (IX):

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula (IXa) or (IXb):

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula (X):

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,R^(w), and L¹ is as defined above and described in embodiments herein,both singly and in combination, with the proviso that L¹ is not—NH—C(O)— or —O—CH₂—.

In some embodiments, the present invention provides a compound ofFormula (Xa):

or a pharmaceutically acceptable salt thereof, wherein each of Ring Band R^(w) is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound ofFormula (XI):

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,Ring B, and L¹ is as defined above and described in embodiments herein,both singly and in combination, with the proviso that Ring B is not

In some embodiments, Ring B is an optionally substituted 6-, 7-, 8-, 9-,or 10-membered bicyclic heterocyclic ring having 1, 2, 3, 4, or 5heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring B is an optionally substituted 6-memberedbicyclic heterocyclic ring having 1 nitrogen.

In some embodiments, the present invention provides a compound ofFormula (XII):

or a pharmaceutically acceptable salt thereof, wherein each of R^(w) andL¹ is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound ofFormula (XIIa) or (XIIb):

or a pharmaceutically acceptable salt thereof, wherein each of R^(w) andL¹ is as defined above and described in embodiments herein, both singlyand in combination.

In some embodiments, the present invention provides a compound ofFormula (XIII):

or a pharmaceutically acceptable salt thereof, wherein each of Ring Aand L¹ is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound ofFormula (XIIIa) or (XIIIb):

or a pharmaceutically acceptable salt thereof, wherein each of Ring Aand L¹ is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound ofFormula (XIV):

or a pharmaceutically acceptable salt thereof, wherein each of Ring Band L¹ is as defined above and described in embodiments herein, bothsingly and in combination. In some embodiments, L¹ is —CH₂—.

In some embodiments, the present invention provides a compound ofFormula (XV):

or a pharmaceutically acceptable salt thereof, wherein L¹ is as definedabove and described in embodiments herein.

In some embodiments, the present invention provides a compound ofFormula (XVa) or (XVb):

or a pharmaceutically acceptable salt thereof, wherein L¹ is as definedabove and described in embodiments herein.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-337

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-368

I-369

I-370

I-371

I-372

I-373

I-374

I-375

I-376

I-377

I-378

I-379

I-380

I-381

I-382

I-385

I-386

I-387

I-388

I-389

I-391

I-392

I-393

I-394

I-395

I-397

I-398

I-399

I-400

I-402

I-403

I-404

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the present invention is not acompound selected from:

The compounds of this invention can be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein. In some embodiments, the present invention provides anintermediate compound described in the Examples, or a salt thereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of this invention or apharmaceutically acceptable derivative thereof and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. The amount of compound incompositions of this invention is such that is effective to measurablyinhibit TEAD, or a variant or mutant thereof, in a biological sample orin a patient. In certain embodiments, the amount of compound incompositions of this invention is such that is effective to measurablyinhibit TEAD, or a variant or mutant thereof, in a biological sample orin a patient. In certain embodiments, a composition of this invention isformulated for administration to a patient in need of such composition.In some embodiments, a composition of this invention is formulated fororal administration to a patient.

The terms “patient” or “subject” as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof TEAD, or a variant or mutant thereof.

Compositions of the present invention can be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention cancan be aqueous or oleaginoussuspension. These suspensions cancan be formulated according totechniques known in the art using suitable dispersing or wetting agentsand suspending agents. The sterile injectable preparation cancan also bea sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil can be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions can also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms can also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention can be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents can also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention can be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention can also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches can also be used.

For topical applications, provided pharmaceutically acceptablecompositions can be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionscan be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions can be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention can also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and can be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations canbe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that can be combinedwith the carrier materials to produce a composition in a single dosageform varies depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient depends upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, rate ofexcretion, drug combination, and the judgment of the treating physicianand the severity of the particular disease being treated. The amount ofa compound of the present invention in the composition also depends uponthe particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

The Hippo Signaling Network

The Hippo signaling network (also known as the Salvador/Warts/Hippo(SWH) pathway) is a master regulator of cell proliferation, death, anddifferentiation. In some embodiments, the main function of the Hipposignaling pathway is to regulate negatively the transcriptionalco-activators Yes-associated protein (YAP) and its paralogue, thetranscriptional co-activator with PDZ-binding motif (TAZ; also known asWWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ bypromoting its cytoplasmic retention and degradation, thereby inhibitingthe growth promoting function regulated under the YAP/TAZ control. In anun-phosphorylated/de-phosphorylated state, YAP, also known as YAP1 orYAP65, together with TAZ, are transported into the nucleus where theyinteract with TEAD family of transcription factors to upregulate genesthat promote proliferation and migration, and inhibit apoptosis. In someinstances, unregulated upregulation of these genes involved inproliferation, migration, and anti-apoptosis leads to development ofcancer. In some instances, overexpression of YAP/TAZ is associated withcancer.

Additional core members of the Hippo signaling pathway comprise theserine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila),Lats1/2 (homologues of Warts/Wts), and their adaptor proteins Sav1(homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues ofMats), respectively. In general, MST1/2 kinase complexes with thescaffold protein Sav1, which in turn phosphorylates and activatesLats1/2 kinase. Lats1/2 is also activated by the scaffold protein Mob.The activated Lats1/2 then phosphorylates and inactivates YAP or itsparalog TAZ. The phosphorylation of YAP/TAZ leads to their nuclearexport, retention within the cytoplasm, and degradation by the ubiquitinproteasome system.

In some instances, Lats1/2 phosphorylates YAP at the [HXRXXS] (SEQ IDNO: 9) consensus motifs. YAP comprises five [HXRXXS] (SEQ ID NO: 9)consensus motifs, wherein X denotes any amino acid residue. In someinstances, Lats1/2 phosphorylates YAP at one or more of the consensusmotifs. In some instances, Lats1/2 phosphorylates YAP at all five of theconsensus motifs. In some instances, Lats1/2 phosphorylate at the S127amino acid position. The phosphorylation of YAP S127 promotes 14-3-3protein binding and results in cytoplasmic sequestration of YAP.Mutation of YAP at the S127 position thereby disrupts its interactionwith 14-3-3 and subsequently promotes nuclear translocation.

Additional phosphorylation occurs at the S381 amino acid position inYAP. Phosphorylation of YAP at the S381 position and on thecorresponding site in TAZ primes both proteins for furtherphosphorylation events by CK16/F in the degradation motif, which thensignals for interaction with the β-TRCP E3 ubiquitin ligase, leading topolyubiquitination and degradation of YAP.

In some instances, Lats1/2 phosphorylates TAZ at the [HXRXXS] (SEQ IDNO: 9) consensus motifs. TAZ comprises four [HXRXXS] (SEQ ID NO: 9)consensus motifs, wherein X denotes any amino acid residues. In someinstances, Lats1/2 phosphorylates TAZ at one or more of the consensusmotifs. In some instances, Lats1/2 phosphorylates TAZ at all four of theconsensus motifs. In some instances, Lats1/2 phosphorylate at the S89amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3protein binding and results in cytoplasmic sequestration of TAZ.Mutation of TAZ at the S89 position thereby disrupts its interactionwith 14-3-3 and subsequently promotes nuclear translocation.

In some embodiments, phosphorylated YAP/TAZ accumulates in thecytoplasm, and undergoes SCF^(β-TRCP)-mediated ubiquitination andsubsequent proteasomal degradation. In some instances, the Skp, Cullin,F-box containing complex (SCF complex) is a multi-protein E3 ubiquitinligase complex that comprises a F-box family member protein (e.g.,Cdc4), Skp1, a bridging protein, and RBX1, which contains a small RINGFinger domain which interacts with E2-ubiquitin conjugating enzyme. Insome cases, the F-box family comprises more than 40 members, in whichexemplary members include F-box/WD repeat-containing protein 1A (FBXW1A,PTrCP1, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phasekinase-associated proteins 2 (SKP2). In some embodiments, the SCFcomplex (e.g., SCF^(βTrcP1)) interacts with an E1 ubiquitin-activatingenzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transferof ubiquitin to the YAP/TAZ substrate. Exemplary E1 ubiquitin-activatingenzymes include those encoded by the following genes: UBA1, UBA2, UBA3,UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2ubiquitin-conjugating enzymes include those encoded by the followinggenes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2,UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K,UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2,UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. Insome embodiments, the ubiquitinated YAP/TAZ further undergoes thedegradation process through the 26S proteasome.

In some embodiments, the Hippo pathway is regulated upstream by severaldifferent families of regulators. In some instances, the Hippo pathwayis regulated by the G-protein and its coupled receptors, the Crumbscomplex, regulators upstream of the MST kinases, and the adherensjunction.

YAP/TAZ Interaction with TEAD

In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZaccumulates in the nucleus. Within the nucleus, YAP/TAZ interacts withthe TEAD family of transcription factors (e.g., human TEAD1 (UniProt KBID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ IDNO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and humanTEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4)) to activate genes involved inanti-apoptosis and proliferation, such as, for example, CTFG, Cyr61, andFGF1.

Proteomic and biochemical studies have shown that the TEAD (TEA Domain)transcription factors are palmitoylated at evolutionarily conservedcysteine residues. Three cysteine residues were found that areevolutionarily conserved and mutated to serine in human TEAD1 (C53S,C327S and C359S) to test whether the mutation affects TEAD1palmitoylation. The C359S mutant showed the greatest loss ofpalmitoylation, and C327S and C53S also showed decreased palmitoylation.These results suggest that C359 plays a critical role in TEAD1palmitoylation. Furthermore, combination mutation of all three cysteineresidues, C53/327/359S (3CS), completely ablated TEAD1 palmitoylation,indicating that these residues are involved in TEAD1 palmitoylation. Ithas been found that TEADs undergo PAT-independent autopalmitoylation,under physiological concentrations of palmitoy 1-CoA. Furthermore,autopalmitoylation plays critical roles in regulating TEAD-YAPassociation and their physiological functions in vitro and in vivo.Chan, et al. Nature Chem. Biol. 12, pages 282-289 (2016); Noland, et al.Structure, 24, 1-8 (2016); Gibault et al. J. Med. Chem. 61, 5057-5072(2018). Therefore, palmitoylation of TEADs play important roles inregulating Hippo pathway transcriptional complexes.

In some embodiments, the compounds disclosed herein modulate theinteraction between YAP/TAZ and TEAD. In some embodiments, the compoundsdisclosed herein bind to TEAD, YAP, or TAZ and prevent the interactionbetween YAP/TAZ and TEAD.

In some embodiments, the compounds described herein irreversibly inhibita TEAD transcription factor. In some embodiments, the transcriptionfactor is TEAD1. In some embodiments, the transcription factor is TEAD2.In some embodiments, the transcription factor is TEAD3. In someembodiments, the transcription factor is TEAD4. In some embodiments, thecompounds described herein covalently bind to the TEAD transcriptionfactor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). In some embodiments, thecompounds described herein irreversibly inhibit the activity of a TEADtranscription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). In someembodiments, the compounds described herein covalently inhibit theactivity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3,and/or TEAD4).

In some embodiments, the compounds disclosed herein bind to TEAD1 anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD2 and disrupt orinhibit the interaction between YAP and TEAD2. In some embodiments, thecompounds disclosed herein bind to TEAD3 and disrupt or inhibit theinteraction between YAP and TEAD3. In some embodiments, the compoundsdisclosed herein bind to TEAD4 and disrupt or inhibit the interactionbetween YAP and TEAD4.

In some embodiments, the compounds disclosed herein bind to TEAD1 anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 at C359, anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 at C53, anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 at C327, anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 at C405, anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 at C359 andC327, and disrupt or inhibit the interaction between YAP and TEAD1. Insome embodiments, the compounds disclosed herein bind to TEAD1 at C359and C53, and disrupt or inhibit the interaction between YAP and TEAD1.In some embodiments, the compounds disclosed herein bind to TEAD1 at C53and C327, and disrupt or inhibit the interaction between YAP and TEAD1.In some embodiments, the compounds disclosed herein bind to TEAD1 atC359 and C405, and disrupt or inhibit the interaction between YAP andTEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1at C53 and C405, and disrupt or inhibit the interaction between YAP andTEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1at C327 and C405, and disrupt or inhibit the interaction between YAP andTEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1at C359, C327, and C53, and disrupt or inhibit the interaction betweenYAP and TEAD1. In some embodiments, the compounds disclosed herein bindto TEAD1 at C359, C327, and C405, and disrupt or inhibit the interactionbetween YAP and TEAD1. In some embodiments, the compounds disclosedherein bind to TEAD1 at C359, C353, and C405, and disrupt or inhibit theinteraction between YAP and TEAD1. In some embodiments, the compoundsdisclosed herein bind to TEAD1 at C327, C53, and C405, and disrupt orinhibit the interaction between YAP and TEAD1. In some embodiments, thecompounds disclosed herein bind to TEAD1 at C359, C327, C53, and C405,and disrupt or inhibit the interaction between YAP and TEAD1.

In some embodiments, the compounds disclosed herein bind to TEAD,prevent TEAD palmitoylation, and disrupt or inhibit the interactionbetween YAP and TEAD. In some embodiments, the compounds disclosedherein bind to TEAD1 and prevent TEAD1 palmitoylation. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C359. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53.In some embodiments, the compounds disclosed herein bind to TEAD1 andprevent TEAD1 palmitoylation at C327. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405.In some embodiments, the compounds disclosed herein bind to TEAD1 andprevent TEAD1 palmitoylation at C359 and C327. In some embodiments, thecompounds disclosed herein bind to TEAD1 and prevent TEAD1palmitoylation at C359 and C53. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53and C327. In some embodiments, the compounds disclosed herein bind toTEAD1 and prevent TEAD1 palmitoylation at C359 and C405. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C53 and C405. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327and C405. In some embodiments, the compounds disclosed herein bind toTEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C359, C327, and C405. In some embodiments, thecompounds disclosed herein bind to TEAD1 and prevent TEAD1palmitoylation at C359, C353, and C405. In some embodiments, thecompounds disclosed herein bind to TEAD1 and prevent TEAD1palmitoylation at C327, C53, and C405. In some embodiments, thecompounds disclosed herein bind to TEAD1 and prevent TEAD1palmitoylation at C359, C327, C53, and C405.

In some embodiments, the compounds disclosed herein bind to TEAD1,prevent TEAD1 palmitoylation, and disrupt or inhibit the interactionbetween YAP and TEAD1. In some embodiments, the compounds disclosedherein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C53, and disrupt or inhibit the interactionbetween YAP and TEAD1. In some embodiments, the compounds disclosedherein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, anddisrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C405, and disrupt or inhibit the interactionbetween YAP and TEAD1. In some embodiments, the compounds disclosedherein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327,and disrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C359 and C53, and disrupt or inhibit theinteraction between YAP and TEAD1. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53and C327, and disrupt or inhibit the interaction between YAP and TEAD1.In some embodiments, the compounds disclosed herein bind to TEAD1 andprevent TEAD1 palmitoylation at C359 and C405, and disrupt or inhibitthe interaction between YAP and TEAD1. In some embodiments, thecompounds disclosed herein bind to TEAD1 and prevent TEAD1palmitoylation at C53 and C405, and disrupt or inhibit the interactionbetween YAP and TEAD1. In some embodiments, the compounds disclosedherein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405,and disrupt or inhibit the interaction between YAP and TEAD1. In someembodiments, the compounds disclosed herein bind to TEAD1 and preventTEAD1 palmitoylation at C359, C327, and C53, and disrupt or inhibit theinteraction between YAP and TEAD1. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359,C327, and C405, and disrupt or inhibit the interaction between YAP andTEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1and prevent TEAD1 palmitoylation at C359, C353, and C405, and disrupt orinhibit the interaction between YAP and TEAD1. In some embodiments, thecompounds disclosed herein bind to TEAD1 and prevent TEAD1palmitoylation at C327, C53, and C405, and disrupt or inhibit theinteraction between YAP and TEAD1. In some embodiments, the compoundsdisclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359,C327, C53, and C405, and disrupt or inhibit the interaction between YAPand TEAD1.

In some embodiments, the compounds disclosed herein bind to TEAD2 atC380, and disrupt or inhibit the interaction between YAP and TEAD2.

In some embodiments, the compounds disclosed herein bind to TEAD2 andprevent TEAD2 palmitoylation. In some embodiments, the compoundsdisclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380.

In some embodiments, the compounds disclosed herein bind to TEAD2,prevent TEAD2 palmitoylation, and disrupt or inhibit the interactionbetween YAP and TEAD2. In some embodiments, the compounds disclosedherein bind to TEAD2 and prevent TEAD2 palmitoylation at C380, anddisrupt or inhibit the interaction between YAP and TEAD2.

In some embodiments, the compounds disclosed herein bind to TEAD3 atC371, and disrupt or inhibit the interaction between YAP and TEAD3. Insome embodiments, the compounds disclosed herein bind to TEAD3 at C368,and disrupt or inhibit the interaction between YAP and TEAD3. In someembodiments, the compounds disclosed herein bind to TEAD3 at C371 andC368, and disrupt or inhibit the interaction between YAP and TEAD3.

In some embodiments, the compounds disclosed herein bind to TEAD3 andprevent TEAD3 palmitoylation. In some embodiments, the compoundsdisclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371.In some embodiments, the compounds disclosed herein bind to TEAD3 andprevent TEAD3 palmitoylation at C368. In some embodiments, the compoundsdisclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368and C371.

In some embodiments, the compounds disclosed herein bind to TEAD3,prevent TEAD3 palmitoylation, and disrupt or inhibit the interactionbetween YAP and TEAD3. In some embodiments, the compounds disclosedherein bind to TEAD3 and prevent TEAD3 palmitoylation at C371, anddisrupt or inhibit the interaction between YAP and TEAD3. In someembodiments, the compounds disclosed herein bind to TEAD3 and preventTEAD3 palmitoylation at C368, and disrupt or inhibit the interactionbetween YAP and TEAD3. In some embodiments, the compounds disclosedherein bind to TEAD3 and prevent TEAD3 palmitoylation at C371 and C368,and disrupt or inhibit the interaction between YAP and TEAD3.

In some embodiments, the compounds disclosed herein bind to TEAD4 atC367, and disrupt or inhibit the interaction between YAP and TEAD4.

In some embodiments, the compounds disclosed herein bind to TEAD4 andprevent TEAD4 palmitoylation. In some embodiments, the compoundsdisclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367.

In some embodiments, the compounds disclosed herein bind to TEAD4,prevent TEAD4 palmitoylation, and disrupt or inhibit the interactionbetween YAP and TEAD4. In some embodiments, the compounds disclosedherein bind to TEAD4 and prevent TEAD4 palmitoylation at C367, anddisrupt or inhibit the interaction between YAP and TEAD4.

YAP/TAZ Regulation Mediated by G-Proteins/GPCRs

In some embodiments, the Hippo pathway is regulated by the Gprotein-coupled receptor (GPCR) and G protein (also known as guaninenucleotide-binding proteins) family of proteins. G proteins aremolecular switches that transmit extracellular stimuli into the cellthrough GPCRs. In some instances, there are two classes of G proteins:monomeric small GTPases and heterotrimeric G protein complexes. In someinstances, the latter class of complexes comprise of alpha (G_(α)), beta(G_(β)), and gamma (G_(γ)) subunits. In some cases, there are severalclasses of G_(α) subunits: G_(q/11)α, G_(12/13)α, G_(i/o)α (Ginhibitory, G other), and G_(s)α (G stimulatory).

In some instances, Giα (G inhibitory), G_(o)α (G other), G_(q)/11α, andG12/13α coupled GPCRs activate YAP/TAZ and promote nucleartranslocation. In other instances, G_(s)α (G stimulatory) coupled GPCRssuppress YAP/TAZ activity, leading to YAP/TAZ degradation.

In some cases, G_(i)α (G inhibitory), G_(o)α (G other), G_(q/11)α, andG_(12/13)α coupled GPCRs activate YAP/TAZ through repression of Lats1/2activities. In contrast, G_(s)α, in some embodiments, induces Lats1/2activity, thereby promoting YAP/TAZ degradation.

G_(q) Family

G_(q)α (also known as G_(q/11) protein), participates in the inositoltrisphosphate (IP₃) signal transduction pathway and calcium (Ca²⁺)release from intracellular storage through the activation ofphospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol4,5-bisphosphate (PIP₂) to diacyl glycerol (DAG) and IP₃. In someinstances, IP₃ then diffuses through the cytoplasm into the ER or thesarcoplasmic reticulum (SR) in the case of muscle cells, and then bindsto inositol trisphosphate receptor (InsP3R), which is a Ca²⁺ channel. Insome cases, the binding triggers the opening of the Ca²⁺ channel, andthereby increases the release of Ca²⁺ into the cytoplasm.

In some embodiments, the GPCRs that interact with G_(q)α include, butare not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types5-HT₂ and 5-HT₃; alpha-1 adrenergic receptor; vasopressin type 1receptors 1A and 1B; angiotensin II receptor type 1; calcitoninreceptor; histamine H1 receptor; metabotropic glutamate receptor, groupI; muscarinic receptors M₁, M₃, and M₅; and trace amine-associatedreceptor 1.

In some instances, there are several types of G_(q)α. G_(q), G_(q/11),G_(q/14), and G_(q/15). The G_(q) protein is encoded by GNAQ. G_(q/11)is encoded by GNA11. G_(q/14) is encoded by GNA14. G_(q/15) is encodedby GNA15.

In some instances, mutations or modifications of the G_(q)α genes havebeen associated with cancer. Indeed, studies have shown that mutationsin G_(q)α promote uveal melanoma (UM) tumorigenesis. In some instances,about 80% of UM cases have been detected to contain a mutation in GNAQand/or GNA11.

In some instances, mutations or modifications of the G_(q)α genes havebeen associated with congenital diseases. In some instances, mutationsof G_(q)α have been observed in congenital diseases such as Port-WineStain and/or Sturge-Weber Syndrome. In some instances, about 92% ofPort-Wine stain cases harbors a mutation in GNAQ. In some instances,about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ.

G_(12/13) Family

G_(12/13)α modulates actin cytoskeletal remodeling in cells andregulates cell processes through guanine nucleotide exchange factors(GEFs). GEFs participate in the activation of small GTPases which actsas molecular switches in a variety of intracellular signaling pathways.Examples of small GTPases include the Ras-related GTPase superfamily(e.g., Rho family such as Cdc42), which is involved in celldifferentiation, proliferation, cytoskeletal organization, vesicletrafficking, and nuclear transport.

In some embodiments, the GPCRs that interact with G_(12/13)α include,but are not limited to, purinergic receptors (e.g., P2Y₁, P2Y₂, P2Y₄,P2Y₆); muscarinic acetylcholine receptors M1 and M3; receptors forthrombin [protease-activated receptor (PAR)-1, PAR-2]; thromboxane(TXA2); sphingosine 1-phosphate (e.g., S1P₂, S1P₃, S1P₄ and S1P₅);lysophosphatidic acid (e.g., LPA₁, LPA₂, LPA₃); angiotensin II (AT1);serotonin (5-HT_(2c), and 5-HT₄); somatostatin (sst₅); endothelin(ET_(A) and ET_(B)); cholecystokinin (CCK₁); V_(1a) vasopressinreceptors; D₅ dopamine receptors; fMLP formyl peptide receptors; GAL₂galanin receptors; EP₃ prostanoid receptors; A₁ adenosine receptors; α₁adrenergic receptors; BB₂ bombesin receptors; B₂ bradykinin receptors;calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NK₁tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.

In some instances, G_(12/13)α is further subdivided into G₁₂ and G₁₃types which are encoded by GNA12 and GNA13, respectively.

G_(i/o) Family

G_(i/o)α (G inhibitory, G other) (also known as G_(i)/G_(o) or G_(i)protein) suppresses the production of 3′,5′-cyclic AMP (cAMP) fromadenosine triphosphate (ATP) through an inhibition of adenylate cyclaseactivity, which converts ATP to cAMP.

In some embodiments, the GPCRs that interact with G_(iα) include, butare not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types5-HT₁ and 5-HT₅; muscarinic acetylcholine receptors such as M₂ and M₄;adenosine receptors such as A₁ and A₃; adrenergic receptors such asα_(2A), α_(2B), and α_(2C); apelin receptors; calcium-sensing receptor;cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopaminesD₂, D₃, and D₄; GABA_(B) receptor; glutamate receptors such asmetabotropic glutamate receptor 2 (mGluR2), metabotropic glutamatereceptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4),metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamatereceptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8);histamine receptors such as H₃ and H₄ receptors; melatonin receptorssuch as melatonin receptor type 1 (MT1), melatonin receptor type 2(MT2), and melatonin receptor type 3 (MT3); niacin receptors such asNIACR1 and NIACR2; opioid receptors such as δ, κ, μ, and nociceptinreceptors 3 (EP₃); prostaglandin receptors such as prostaglandin Ereceptor 1 (EP₁), prostaglandin E receptor 3 (EP₃), prostaglandin Freceptor (FP), and thromboxane receptor (TP); somatostatin receptorssst₁, sst₂, sst₃, sst₄, and sst₅; and trace amine-associated receptor 8.

In some instances, there are several types of G_(i)α. G_(i)α1, G_(i)α2,G_(i)α3, G_(i)α4, G_(o)α, G_(t), G_(gust), and G_(z). G_(i)α1 is encodedby GNAI1. G_(i)α2 is encoded by GNAI2. G_(i)α3 is encoded by GNAI3.G_(o)α, the α_(o) subunit, is encoded by GNAO1. G_(t) is encoded byGNAT1 and GNAT2. G_(gust) is encoded by GNAT3. G_(z) is encoded by GNAZ.

G_(s) Family

G_(s)α (also known as G stimulatory, G_(s) alpha subunit, or G_(s)protein) activates the cAMP-dependent pathway through the activation ofadenylate cyclase, which convers adenosine triphosphate (ATP) to3′,5′-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, theGPCRs that interact with G_(s)α include, but are not limited to,5-hydroxytryptamine receptor (5-HT receptor) types 5-HT₄, 5-HT₆, and5-HT₇; adrenocorticotropic hormone receptor (ACTH receptor) (also knownas melanocortin receptor 2 or MC2R); adenosine receptor types A_(2a) andA_(2b); arginine vasopressin receptor 2 (AVPR2); β-adrenergic receptorsβ₁, β₂, and β₃; calcitonin receptor; calcitonin gene-related peptidereceptor; corticotropin-releasing hormone receptor; dopamine receptorD1-like family receptors such as D₁ and D₅; follicle-stimulating hormonereceptor (FSH-receptor); gastric inhibitory polypeptide receptor;glucagon receptor; histamine H₂ receptor; luteinizinghormone/choriogonadotropin receptor; melanocortin receptors such asMC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1;prostaglandin receptor types D₂ and I₂; secretin receptor; thyrotropinreceptor; trace amine-associated receptor 1; and box jellyfish opsin.

In some instances, there are two types of G_(s)α: G_(s) and G_(olf).G_(s) is encoded by GNAS. G_(olf) is encoded by GNAL.

Additional Regulators of the Hippo Signaling Network

In some embodiments, the additional regulator of the Hippo signalingpathway is the Crumbs (Crb) complex. The Crumbs complex is a keyregulator of cell polarity and cell shape. In some instances, the Crumbscomplex comprises transmembrane CRB proteins which assemblemulti-protein complexes that function in cell polarity. In someinstances, CRB complexes recruit members of the Angiomotin (AMOT) familyof adaptor proteins that interact with the Hippo pathway components. Insome instances, studies have shown that AMOT directly binds to YAP,promotes YAP phosphorylation, and inhibits its nuclear localization.

In some instances, the additional regulator of the Hippo signalingpathway comprises regulators of the MST kinase family. MST kinasesmonitor actin cytoskeletal integrity. In some instances, the regulatorsinclude TAO kinases and cell polarity kinase PAR-1.

In some instances, the additional regulator of the Hippo signalingpathway comprises molecules of the adherens junction. In some instances,E-Cadherin (E-cad) suppresses YAP nuclear localization and activitythrough regulating MST activity. In some embodiments, E-cad-associatedprotein a-catenin regulates YAP through sequestering YAP/14-3-3complexes in the cytoplasm. In other instances, Ajuba protein familymembers interact with Lats1/2 kinase activity, thereby preventinginactivation of YAP/TAZ.

In some embodiments, additional proteins that interact with YAP/TAZeither directly or indirectly include, but are not limited to, Merlin,protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-induciblekinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discslarge (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.

In some embodiments, the compounds described herein are inhibitors oftranscriptional coactivator with PDZ binding motif/Yes-associatedprotein transcriptional coactivator (TAZ/YAP). In some embodiments, thecompounds described herein increase the phosphorylation oftranscriptional coactivator with PDZ binding motif/Yes-associatedprotein transcriptional coactivator (TAZ/YAP) or decrease thedephosphorylation of transcriptional coactivator with PDZ bindingmotif/Yes-associated protein transcriptional coactivator (TAZ/YAP). Insome embodiments, the compounds increase the ubiquitination oftranscriptional coactivator with PDZ binding motif/Yes-associatedprotein transcriptional coactivator (TAZ/YAP) or decrease thedeubiquitination of transcriptional coactivator with PDZ bindingmotif/Yes-associated protein transcriptional coactivator (TAZ/YAP).

In some embodiments, the compounds disclosed herein are inhibitors ofone or more of the proteins encompassed by, or related to, the Hippopathway. In some embodiments, an inhibitor of the Hippo pathway is aninhibitor of a G-protein and/or its coupled GPCR. In some embodiments,an inhibitor of the Hippo pathway is an inhibitor of a G-protein. Insome embodiments, an inhibitor of the Hippo pathway is an inhibitor ofthe G_(q)α family proteins such as G_(q), G_(q/11), G_(q/14), andG_(q/15); the G_(12/13)α family of proteins such as G1 and G_(i)α; orthe G_(i)α family of proteins such as G_(i)α1, G_(i)α2, G_(i)α3,G_(i)α4, G_(o)α, G_(t), G_(gust), and G_(z). In some embodiments, aninhibitor of the Hippo pathway is an inhibitor of G_(q). In someembodiments, an inhibitor of the Hippo pathway is an inhibitor ofG_(q/11). In some embodiments, an inhibitor of the Hippo pathway is aninhibitor of G_(q/14). In some embodiments, an inhibitor of the Hippopathway is an inhibitor of Guns. In some embodiments, an inhibitor ofthe Hippo pathway is an inhibitor of G₁₂. In some embodiments, aninhibitor of the Hippo pathway is an inhibitor of G₁₃. In someembodiments, an inhibitor of the Hippo pathway is an inhibitor ofG_(i)α1. In some embodiments, an inhibitor of the Hippo pathway is aninhibitor of G_(i)α2. In some embodiments, an inhibitor of the Hippopathway is an inhibitor of G_(i)α3. In some embodiments, an inhibitor ofthe Hippo pathway is an inhibitor of G_(i)α4. In some embodiments, aninhibitor of the Hippo pathway is an inhibitor of G_(o)α. In someembodiments, an inhibitor of the Hippo pathway is an inhibitor of G_(t).In some embodiments, an inhibitor of the Hippo pathway is an inhibitorof G_(gust). In some embodiments, an inhibitor of the Hippo pathway isan inhibitor of G_(z).

In some embodiments, an inhibitor of the Hippo pathway is an inhibitorof a core protein of the Hippo pathway. In some embodiments, aninhibitor of the Hippo pathway is an inhibitor of Sav1. In someembodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob.In some embodiments, an inhibitor of the Hippo pathway is an inhibitorof YAP. In some embodiments, an inhibitor of the Hippo pathway is aninhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathwayis an inhibitor of TEAD.

In some embodiments, an inhibitor of the Hippo pathway is an inhibitorof a protein associated with the ubiquitination and proteasomaldegradation pathway. In some embodiments, an inhibitor of the Hippopathway is an inhibitor of a proteasomal degradation pathway protein(e.g., 26S proteasome).

In some embodiments, an inhibitor of the Hippo pathway is an inhibitorof a protein of the Ras superfamily of proteins. In some embodiments, aninhibitor of the Hippo pathway is an inhibitor of a protein of the Rhofamily of proteins. In some embodiments, an inhibitor of the Hippopathway is an inhibitor of Cdc42.

Cdc42 is a member of the Ras superfamily of small GTPases. Specifically,Cdc42 belongs to the Rho family of GTPases, in which the family membersparticipate in diverse and critical cellular processes such as genetranscription, cell-cell adhesion, and cell cycle progression. Cdc42 isinvolved in cell growth and polarity, and in some instances, Cdc42 isactivated by guanine nucleotide exchange factors (GEFs). In some cases,an inhibitor of Cdc42 is a compound disclosed herein.

In some embodiments, an inhibitor of the Hippo pathway is an inhibitorof a deubiquitinating enzyme. In some embodiments, an inhibitor of theHippo pathway is an inhibitor of a cysteine protease or ametalloprotease. In some embodiments, an inhibitor of the Hippo pathwayis an inhibitor of an ubiquitin-specific protease. USP47 is a member ofthe ubiquitin-specific protease (USP/UBP) superfamily of cysteineproteases. In some embodiments, the compounds disclosed herein areinhibitors of USP47.

In some embodiments, the present invention provides a use of a compound,or a pharmaceutical salt or composition thereof, for treating one ormore disorders, diseases, and/or conditions wherein the disorder,disease, or condition includes, but is not limited to, a cellularproliferative disorder.

The activity of a compound utilized in this invention as an inhibitor ofTEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutantthereof, can be assayed in vitro, in vivo or in a cell line. In vitroassays include assays that determine inhibition of TEAD (e.g., TEAD1,TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof. Alternatein vitro assays quantitate the ability of the inhibitor to bind to TEAD(e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutantthereof. Detailed conditions for assaying a compound utilized in thisinvention as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/orTEAD4), or a variant or mutant thereof, are set forth in the Examplesbelow. See, for example, Examples 2 and 5.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment can be administeredafter one or more symptoms have developed. In other embodiments,treatment can be administered in the absence of symptoms. For example,treatment can be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment can also becontinued after symptoms have resolved, for example, to prevent or delaytheir recurrence.

The provided compounds are inhibitors of TEAD (e.g., TEAD1, TEAD2,TEAD3, and/or TEAD4) and are therefore useful for treating one or moredisorders associated with activity of TEAD (e.g., TEAD1, TEAD2, TEAD3,and/or TEAD4). Thus, in certain aspects and embodiments, the presentinvention provides a method for treating a TEAD-mediated disordercomprising the step of administering to a patient in need thereof atherapeutically effective compound of the present invention, orpharmaceutically acceptable composition thereof.

As used herein, the term “TEAD-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or avariant or mutant thereof, is known to play a role. Accordingly, anotheraspect or embodiment of the present invention relates to treating orlessening the severity of one or more diseases in which TEAD (e.g.,TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, areknown to play a role.

As used herein, the term “a therapeutically effective amount of” refersto the amount of a TEAD inhibitor or a pharmaceutically acceptable saltthereof, which is effective to reduce or attenuate the biologicalactivity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variantor mutant thereof, provide a therapeutic benefit in the treatment of acondition, or to delay or minimize one or more symptoms associated withthe condition in a biological sample or in a patient. In someembodiments, “a therapeutically effective amount of” refers to theamount of a TEAD inhibitor or a pharmaceutically acceptable salt thereofthat measurably decreases the binding or signaling activity of TEAD(e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutantthereof or any TEAD-mediated activity. The term “therapeuticallyeffective amount” can encompass, in some embodiments, an amount thatimproves overall therapy, reduces or avoids symptoms, signs, or causesof the condition, and/or enhances the therapeutic efficacy of anothertherapeutic agent. In certain embodiments, a therapeutically effectiveamount is an amount sufficient for inhibition of a TEAD transcriptionfactor. In certain embodiments, a therapeutically effective amount is anamount sufficient for treating a proliferative disease.

In some aspects and embodiments, provided herein are methods oftreating, reducing the severity of, delaying the onset of, or inhibitingthe progress of a disease or disorder, or one or more symptoms thereofof a disease or disorder characterized by or associated with increasedTEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/orincreased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activitycomprising the step of administering to a patient in need thereof atherapeutically effective compound of the present invention, orpharmaceutically acceptable composition thereof. In some aspects andembodiments, provided herein are methods of treating, reducing theseverity of, delaying the onset of, or inhibiting the progress of adisease or disorder, or one or more symptoms thereof of a disease ordisorder in which inhibition or antagonizing of TEAD (e.g., TEAD1,TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the stepof administering to a patient in need thereof a therapeuticallyeffective compound of the present invention, or pharmaceuticallyacceptable composition thereof. In some aspects and embodiments,provided herein are methods of treating, reducing the severity of,delaying the onset of, or inhibiting the progress of a disease ordisorder, or one or more symptms thereof of a disease or disorder inwhich inhibition or antagonizing of the Hippo pathway is beneficialcomprising the step of administering to a patient in need thereof atherapeutically effective compound of the present invention, orpharmaceutically acceptable composition thereof.

In some aspects and embodiments, the present invention provides a methodfor treating one or more disorders, diseases, and/or conditions whereinthe disorder, disease, or condition includes, but is not limited to, acellular proliferative disorder, comprising administering to a patientin need thereof, a TEAD inhibitor compound as described herein, or apharmaceutical salt or composition thereof. In some embodiments, acellular proliferative disorder is cancer. In some embodiments, thecancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3,and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2,TEAD3, and/or TEAD4) activity.

As used herein, the terms “increased,” “elevated,” or “enhanced,” areused interchangeably and encompass any measurable increase in abiological function and/or biological activity and/or a concentration.For example, an increase can be by at least about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%,about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold,about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold,about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher,relative to a control or baseline amount of a function, or activity, orconcentration.

As used herein, the terms “increased expression” and/or “increasedactivity” of a substance, such as TEAD, in a sample or cancer or patientrefers to an increase in the amount of the substance, such as TEAD, ofabout 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about50-fold, about 100-fold, or higher, relative to the amount of thesubstance, such as TEAD, in a control sample or control samples, such asan individual or group of individuals who are not suffering from thedisease or disorder (e.g., cancer) or an internal control, as determinedby techniques known in the art. A subject can also be determined to havean “increased expression” or “increased activity” of TEAD if theexpression and/or activity of TEAD is increased by one standarddeviation, two standard deviations, three standard deviations, fourstandard deviations, five standard deviations, or more, relative to themean (average) or median amount of TEAD in a control group of samples ora baseline group of samples or a retrospective analysis of patientsamples. As practiced in the art, such control or baseline expressionlevels can be previously determined, or measured prior to themeasurement in the sample or cancer or subject, or can be obtained froma database of such control samples.

As used herein, a “proliferative disease” refers to a disease thatoccurs due to abnormal growth or extension by the multiplication ofcells (Walker, Cambridge Dictionary of Biology, Cambridge UniversityPress: Cambridge, UK, 1990). A proliferative disease can be associatedwith: 1) the pathological proliferation of normally quiescent cells; 2)the pathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes, such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

Cancer

The cancer or proliferative disorder or tumor to be treated using thecompounds and methods and uses described herein include, but are notlimited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, aneurological cancer, skin cancer, breast cancer, a prostate cancer, acolorectal cancer, lung cancer, head and neck cancer, a gastrointestinalcancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, abone cancer, renal cancer, and a vascular cancer.

In some embodiments of the methods and uses described herein, a canceris mediated by activation of transcriptional coactivator with PDZbinding motif/Yes-associated protein transcription coactivator(TAZ/YAP). In some embodiments of the methods and uses described herein,a cancer is mediated by modulation of the interaction of YAP/TAZ withTEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). In some embodiments ofthe methods and uses described herein, the cancer is characterized by orassociated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4)expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/orTEAD4) activity. In some embodiments of the methods and uses describedherein, the cancer is a cancer in which YAP is localized in the nucleusof the cancer cells.

In some embodiments, a cancer is characterized by a mutant Gα-protein.In some embodiments, a mutant Gα-protein is selected from G12, G13, Gq,G11, Gi, Go, and Gs. In some embodiments, a mutant Gα-protein is G12. Insome embodiments, a mutant Gα-protein is G13. In some embodiments, amutant Gα-protein is Gq. In some embodiments, a mutant Gα-protein isG11. In some embodiments, a mutant Gα-protein is Gi. In someembodiments, a mutant Gα-protein is Go. In some embodiments, a mutantGα-protein is Gs.

In some embodiments of the methods and uses described herein, a canceris treated by inhibiting or reducing or decreasing or arresting furthergrowth or spread of the cancer or tumor. In some embodiments of themethods and uses described herein, a cancer is treated by inhibiting orreducing the size (e.g., volume or mass) of the cancer or tumor by atleast 5%, at least 10%, at least 25%, at least 50%, at least 75%, atleast 90% or at least 99% relative to the size of the cancer or tumorprior to treatment. In some embodiments of the methods and usesdescribed herein, a cancer is treated by reducing the quantity of thecancers or tumors in the patient by at least 5%, at least 10%, at least25%, at least 50%, at least 75%, at least 90% or at least 99% relativeto the quantity of the cancers or tumors prior to treatment.

In some embodiments of the methods and uses described herein, the canceris lung cancer, thyroid cancer, ovarian cancer, colorectal cancer,prostate cancer, cancer of the pancreas, cancer of the esophagus, livercancer, breast cancer, skin cancer, or mesothelioma. In someembodiments, the cancer is mesothelioma, such as malignant mesothelioma.In some embodiments, cancer includes, without limitation, leukemias(e.g., acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemia, acute myeloblastic leukemia, acute promyelocytic leukemia,acute myelomonocytic leukemia, acute monocytic leukemia, acuteerythroleukemia, chronic leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin'sdisease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia,multiple myeloma, heavy chain disease, and solid tumors such as sarcomasand carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,glioblastoma multiforme (GBM, also known as glioblastoma),medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma,neurofibrosarcoma, meningioma, melanoma, neuroblastoma, andretinoblastoma).

In some embodiments, the cancer is glioma, astrocytoma, glioblastomamultiforme (GBM, also known as glioblastoma), medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma,melanoma, neuroblastoma, or retinoblastoma.

In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g.,Grade I—Pilocytic Astrocytoma, Grade II—Low-grade Astrocytoma, GradeIII—Anaplastic Astrocytoma, or Grade IV—Glioblastoma (GBM)), chordoma,CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixedglioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma,metastatic brain tumor, oligodendroglioma, pituitary tumors, primitiveneuroectodermal (PNET) tumor, or schwannoma. In some embodiments, thecancer is a type found more commonly in children than adults, such asbrain stem glioma, craniopharyngioma, ependymoma, juvenile pilocyticastrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor,primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In someembodiments, the patient is an adult human. In some embodiments, thepatient is a child or pediatric patient.

Cancer includes, in another embodiment, without limitation,mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, colon cancer, rectal cancer,cancer of the anal region, stomach cancer, gastrointestinal (gastric,colorectal, and duodenal), uterine cancer, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, testicular cancer,chronic or acute leukemia, chronic myeloid leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, non-Hodgkins's lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocorticalcancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma,fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one ormore of the foregoing cancers.

In some embodiments, the cancer is selected from hepatocellularcarcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tubecancer; papillary serous cystadenocarcinoma or uterine papillary serouscarcinoma (UPSC); prostate cancer; testicular cancer; gallbladdercancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma;rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma;anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer;pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cellcarcinoma of the head and neck (SCCHN); salivary gland cancer; glioma,or brain cancer; neurofibromatosis-1 associated malignant peripheralnerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; ormedulloblastoma.

In some embodiments, the cancer is selected from hepatocellularcarcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovariancancer, ovarian epithelial cancer, fallopian tube cancer, papillaryserous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC),hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma,rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer,adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma,pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associatedmalignant peripheral nerve sheath tumors (MPNST), Waldenstrom'smacroglobulinemia, or medulloblastoma.

In some embodiments, a cancer is a solid tumor, such as a sarcoma,carcinoma, or lymphoma. Solid tumors generally comprise an abnormal massof tissue that typically does not include cysts or liquid areas. In someembodiments, the cancer is selected from renal cell carcinoma, or kidneycancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or livercancer; melanoma; breast cancer; colorectal carcinoma, or colorectalcancer; colon cancer; rectal cancer; anal cancer; lung cancer, such asnon-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC);ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, orfallopian tube cancer; papillary serous cystadenocarcinoma or uterinepapillary serous carcinoma (UPSC); prostate cancer; testicular cancer;gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bonesynovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewingsarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreaticcancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cellcarcinoma of the head and neck (SCCHN); salivary gland cancer; glioma,or brain cancer; neurofibromatosis-1 associated malignant peripheralnerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; ormedulloblastoma.

In some embodiments, the cancer is selected from renal cell carcinoma,hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma,colorectal cancer, colon cancer, rectal cancer, anal cancer, ovariancancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tubecancer, papillary serous cystadenocarcinoma, uterine papillary serouscarcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bonesynovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma,anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer,pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, braincancer, neurofibromatosis-1 associated malignant peripheral nerve sheathtumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellularcarcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovariancancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tubecancer, papillary serous cystadenocarcinoma, uterine papillary serouscarcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bonesynovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroidcancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductalcarcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1associated malignant peripheral nerve sheath tumors (MPNST),Waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is hepatocellular carcinoma (HCC). Insome embodiments, the cancer is hepatoblastoma. In some embodiments, thecancer is colon cancer. In some embodiments, the cancer is rectalcancer. In some embodiments, the cancer is ovarian cancer, or ovariancarcinoma. In some embodiments, the cancer is ovarian epithelial cancer.In some embodiments, the cancer is fallopian tube cancer. In someembodiments, the cancer is papillary serous cystadenocarcinoma. In someembodiments, the cancer is uterine papillary serous carcinoma (UPSC). Insome embodiments, the cancer is hepatocholangiocarcinoma. In someembodiments, the cancer is soft tissue and bone synovial sarcoma. Insome embodiments, the cancer is rhabdomyosarcoma. In some embodiments,the cancer is osteosarcoma. In some embodiments, the cancer isanaplastic thyroid cancer. In some embodiments, the cancer isadrenocortical carcinoma. In some embodiments, the cancer is pancreaticcancer, or pancreatic ductal carcinoma. In some embodiments, the canceris pancreatic adenocarcinoma. In some embodiments, the cancer is glioma.In some embodiments, the cancer is malignant peripheral nerve sheathtumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1associated MPNST. In some embodiments, the cancer is Waldenstrom'smacroglobulinemia. In some embodiments, the cancer is medulloblastoma.

In some embodiments, a cancer is a viral-associated cancer, includinghuman immunodeficiency virus (HIV) associated solid tumors, humanpapilloma virus (HPV)-16 positive incurable solid tumors, and adultT-cell leukemia, which is caused by human T-cell leukemia virus type I(HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemiacharacterized by clonal integration of HTLV-I in leukemic cells (Seeclinicaltrials.gov, study NCT02631746); as well as virus-associatedtumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer,vaginal cancer, vulvar cancer, squamous cell carcinoma of the head andneck, and Merkel cell carcinoma. (See clinicaltrials.gov, studiesNCT02488759, NCT0240886, and NCTO2426892)

In some embodiments, a cancer is melanoma cancer. In some embodiments, acancer is breast cancer. In some embodiments, a cancer is lung cancer.In some embodiments, a cancer is small cell lung cancer (SCLC). In someembodiments, a cancer is non-small cell lung cancer (NSCLC).

The compounds and compositions, according to the methods of the presentinvention, can be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer or tumor. The exact amount required varies from subject tosubject, depending on the species, age, and general condition of thesubject, the severity of the disease or condition, the particular agent,its mode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionis decided by the attending physician within the scope of sound medicaljudgment. The specific effective dose level for any particular patientor organism depends upon a variety of factors, including the disorderbeing treated and the severity of the disorder; the activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The terms “patient” or“subject”, as used herein, means an animal, preferably a mammal, andmost preferably a human.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the disease or disorder beingtreated. In certain embodiments, the compounds of the invention can beadministered orally or parenterally at dosage levels of about 0.01 mg/kgto about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg,of subject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type can also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype can also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Co-Administration with One or More Other Therapeutic Agent(s)

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, can also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

A compound of the current invention can also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides, or in addition, be administered especially for tumortherapy in combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible, as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

One or more other therapeutic agent(s) may be administered separatelyfrom a compound or composition of the invention, as part of a multipledosage regimen. Alternatively, one or more other therapeutic agentsagents (s) be part of a single dosage form, mixed together with acompound of this invention in a single composition. If administered as amultiple dosage regime, one or more other therapeutic agent(s) and acompound or composition of the invention can be administeredsimultaneously, sequentially or within a period of time from oneanother, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. Insome embodiments, one or more other therapeutic agent(s) and a compoundor composition of the invention are administered as a multiple dosageregimen within greater than 24 hours apart.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention can be administered with one or more other therapeuticagent(s) simultaneously or sequentially in separate unit dosage forms ortogether in a single unit dosage form. Accordingly, the presentinvention provides a single unit dosage form comprising a compound ofthe current invention, one or more other therapeutic agent(s), and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of a compound of the invention and one or more othertherapeutic agent(s) (in those compositions which comprise an additionaltherapeutic agent as described above) that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration.Preferably, a composition of the invention should be formulated so thata dosage of between 0.01-100 mg/kg body weight/day of a compound of theinvention can be administered.

In those compositions which comprise one or more other therapeuticagent(s), the one or more other therapeutic agent(s) and a compound ofthe invention may act synergistically. Therefore, the amount of the oneor more other therapeutic agent(s) in such compositions may be less thanthat required in a monotherapy utilizing only that therapeutic agent. Insuch compositions a dosage of between 0.01-1,000 μg/kg body weight/dayof the one or more other therapeutic agent(s) can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent(s) in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent(s) isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approvided for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Other Therapeutic Agents

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib(RUBRACA®, Clovis Oncology); niraparib (ZEJULA@, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®,Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (EPIDAZA®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib(KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

In some embodiments, one or more other therapeutic agent is aplatinum-based therapeutic, also referred to as platins. Platins causecross-linking of DNA, such that they inhibit DNA repair and/or DNAsynthesis, mostly in rapidly reproducing cells, such as cancer cells.

In some embodiments, a platinum-based therapeutic is selected fromcisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®,Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN®Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (PoniardPharmaceuticals); and satraplatin (JM-216, Agennix).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®,Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel(ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, YONDELIS®, Janssen Oncology),mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals);vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals;MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb;GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ER^(w) INAZE®,EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, JEVTANA®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, TREANDA®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib(CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib(LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AGand Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®,Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®,Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis);nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®,BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib(INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®,Genentech/Roche/Astellas); lapatinib (TYKERB®, Novartis); afatinib(GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib(SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, suchas crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); andalectinib (ALECENZa®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (IMBRUVICA®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (RYDAPT®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TKI258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®,Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®,Pfizer).

In some embodiments, one or more other therapeutic agent is a proteasomeinhibitor. Approved proteasome inhibitors useful in the presentinvention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®,Amgen); and ixazomib (NINLARO®, Takeda).

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (ERBITUX®,Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®,Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®,AstraZeneca).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) andletrozole (FEMARA®, Novartis).

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (ODOMZO®,Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (ALIMTTA®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(POTELIGEO®, Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (RITUXAN®,Genentech/BiogenIdec); ofatumumab (anti-CD20, ARZERRA®,GlaxoSmithKline); obinutuzumab (anti-CD20, GAZYVA®, Genentech),ibritumomab (anti-D20 and Yttrium-90, ZEVALIN®, SpectrumPharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics);trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, KADCYLA®, Genentech); andpertuzumab (anti-HER2, PERJETA®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, ADCETRIS®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (ONIVYDE®, MerrimackPharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (PIXUVRI®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (XTANDI®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (EVISTA®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (XGEVA®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor-beta (TGF-beta or TGFB). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA-formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGF3 trap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgG1 antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGFβ “trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agents is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (TEMODAL*); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name AROMASIN™. Formestane is marketed under the trade nameLENTARON™. Fadrozole is marketed under the trade name AFEMA™.Anastrozole is marketed under the trade name ARIMIDEX™. Letrozole ismarketed under the trade names FEMARA™ or FEMAr™ Aminoglutethimide ismarketed under the trade name ORIMETEN™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNOLVADEX™. Raloxifene hydrochloride is marketed under the trade nameEVISTA™ Fulvestrant can be administered under the trade name FASLODEX™Fulvestrant can be administered under the trade name Faslodex™. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin, and goserelin acetate. Goserelin can beadministered under the trade name ZOLADEX™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g., in the formas it is marketed, e.g., under the trademark CAMPTOSAR™. Topotecan ismarketed under the trade name HYCAMPTIN™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as CAELYX™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name ETOPOPHOS™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name ACRIBLASTIN™ or ADRIAMYCIN™ Epirubicin is marketedunder the trade name FARMORUBICIN™. Idarubicin is marketed. under thetrade name ZAVEDOS™. Mitoxantrone is marketed under the trade nameNOVANTRON™.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name TAXOL™ Docetaxel is marketed under thetrade name TAXOTERE™. Vinblastine sulfate is marketed under the tradename VINBLASTIN R.P™. Vincristine sulfate is marketed under the tradename FARMISTIN™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name CYCLOSTIN™.Ifosfamide is marketed under the trade name HOLOXAN™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name XELODA™. Gemcitabine is marketed underthe trade name GEMZAR™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g., underthe trademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ELOXATIN™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g., BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(GLEEVEC™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (HERCEPTIN™), cetuximab(ERBITUX™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g., unrelated to protein or lipid kinaseinhibition e.g., thalidomide (THALOMID™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g., inhibitors of phosphatase 1, phosphatase 2A,or CDCl25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib

(CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name DIDRONEL™. Clodronic acid is marketed under thetrade name BONEFOS™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name AREDIA™.Alendronic acid is marketed under the trade name FOSAMAX™. Ibandronicacid is marketed under the trade name BONDRANAT™. Risedronic acid ismarketed under the trade name ACTONEL™. Zoledronic acid is marketedunder the trade name ZOMETA™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (RAPAMUNE®),everolimus (CERTICAN™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(ZARNESTRA™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (VELCADE™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g.,hydroxamate peptidomimetic inhibitor batimastat and its orallybioavailable analogue marimastat (BB-2516), prinomastat (AG3340),metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B orAAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DM1, erbitux,bevacizumab (AVASTIN™) rituximab (RITUXAN©), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;ANGIOSTATIN™; ENDOSTATIN™; anthranilic acid amides; ZD4190; Zd₆474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (AVASTIN™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as VISUDYNE™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational (e.g., IMS World Publications).

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACl, APRIL, BCMA, LTOR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, W0009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, W0009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Ikena Oncology, formerly known as KynTherapeutics); and NLG-919 (WO09/73620, W0009/1156652, WO11/56652,WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO©,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenolmebutate (PICATO®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidinekinase-(TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-lh68/GLV-lh153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CGO070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TGO1 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June et al.; hereby incorporatedby reference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+(Th17) and CD8+(Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCTO2124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that can be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams et al., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiment, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams et al. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams et al. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. Adamset al.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BITE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BITE®) antibody construct. In someembodiments, a bispecific T cell engager (BITE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BITE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BITE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BITE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BITE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BITE®-actievated T cells. In some embodiment, the bystander cellscomprises tumor-associated antigen (TAA) negatgive cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that can be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include, but are not limited to, Tremelimumab(CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody(Anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224(anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A(anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab(anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include,but are not limited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab

(OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In someembodiments, the checkpoint inhibitor is selected from nivolumab(anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab(anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody,TECENTRIQ®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981); and CTX-471 (CompassTherapeutics), an agonistic anti-CD137 antibody in metastatic or locallyadvanced malignancies (NCT03881488).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KTR) inhibitors. KTR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that can be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Unless otherwisestated, one or more tautomeric forms of compounds of the examplesdescribed hereinafter may be prepared in situ and/or isolated. Alltautomeric forms of compounds of the examples described hereafter shouldbe considered to be disclosed. Temperatures are given in degreescentigrade. If not mentioned otherwise, all evaporations are performedunder reduced pressure, preferably between about 15 mm Hg and 100 mm Hg(=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.,microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR.Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art. Further, the compounds of the present invention can beproduced by organic synthesis methods known to one of ordinary skill inthe art as shown in the following examples.

Example 1: Synthesis of Exemplary Compounds

Certain exemplary compounds are prepared following the followingschemes.

Synthesis of I-5

Synthesis of I-11

Synthesis of I-3

Synthesis of I-13 & I-14

Synthesis of I-15

Synthesis of I-1, I-25, & I-26

Synthesis of I-12, I-23, & I-24

Synthesis of I-22

Synthesis of I-18 & I-19

Synthesis of I-20 & I-21

I-27

Step 1: N-(3-Bromo-4-methyl-phenyl)prop-2-enamide

To a solution of 3-bromo-4-methyl-aniline (1 g, 5.37 mmol, 1 eq) andDIEA (2.08 g, 16.12 mmol, 2.81 mL, 3 eq) in THE (20 mL) was addedprop-2-enoyl chloride (600 mg, 6.63 mmol, 540.54 μL, 1.23 eq) dropwiseat 20° C. The mixture was stirred at 20° C. for 1 h. TLC (PE/EtOAc=1/1,R_(f)=0.30) showed the starting material was consumed completely. Thereaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc(50 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yieldN-(3-bromo-4-methyl-phenyl)prop-2-enamide (1.1 g, 4.42 mmol, 82.2%yield, 96.4% purity) as a yellow solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (br s,1H), 7.43 (d, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.18 (d, J=8.1 Hz, 1H),6.48-6.40 (m, 1H), 6.29-6.19 (m, 1H), 5.78 (dd, J=1.2, 10.3 Hz, 1H),2.36 (s, 3H); ES-LCMS m/z 239.9, 241.9 [M+H]⁺.

Step 2: N-[3-(4-Chloroanilino)-4-methyl-phenyl]prop-2-enamide

A mixture of N-(3-bromo-4-methyl-phenyl)prop-2-enamide (500 mg, 2.01mmol, 1 eq), 4-chloroaniline (300 mg, 2.35 mmol, 1.17 eq), K₂CO₃ (280mg, 2.03 mmol, 1.01 eq), Pd₂(dba)₃ (190 mg, 207.49 μmol, 1.03e-1 eq) andXantphos (190 mg, 328.37 μmol, 1.64e-1 eq) in 1,4-dioxane (10 mL) wasbubbled with N₂ for 2 minutes and sealed. The mixture was irradiatedunder microwave at 110° C. for 30 minutes. TLC (PE/EtOAc=1/1,R_(f)=0.24) showed the starting material was almost consumed. Thereaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(20 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 8/1,TLC: PE/EtOAc=1/1, R_(f)=0.24) to yieldN-[3-(4-chloroanilino)-4-methyl-phenyl]prop-2-enamide (61.35 mg, 208.78μmol, 10.4% yield, 97.6% purity) as a yellow solid. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.48 (s, 1H), 7.26-7.18 (m, 3H), 7.16-7.08 (m, 2H),6.95-6.91 (m, 2H), 6.40 (d, J=16.9 Hz, 1H), 6.20 (dd, J=10.3, 16.9 Hz,1H), 5.74 (d, J=10.2 Hz, 1H), 5.39 (s, 1H), 2.21 (s, 3H); ES-LCMS m/z287.0 [M+H]⁺.

I-28

Step 1: 2-(4-Chlorophenoxy)-1-methyl-3-nitro-benzene

To a solution of 2-fluoro-1-methyl-3-nitro-benzene (500 mg, 3.22 mmol, 1eq) in DMF (20 mL) was added Cs₂CO₃ (3.15 g, 9.67 mmol, 3 eq) and4-chlorophenol (414.36 mg, 3.22 mmol, 316.31 μL, 1 eq). The mixture wasstirred at 120° C. for 12 h. To the mixture was added water (30 mL) andextracted with ethyl acetate (30 mL×3). The combined organic phase waswashed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0, TLC: PE/EtOAc=100/1, R_(f)=0.32) toyield 2-(4-chlorophenoxy)-1-methyl-3-nitro-benzene (820 mg, 2.95 mmol,91.7% yield, 95.0% purity) as yellow oil. ¹H NMR (500 MHz, CD₃OD) δ ppm7.83 (dd, J=1.1, 8.1 Hz, 1H), 7.64 (dd, J=0.7, 7.7 Hz, 1H), 7.43-7.36(m, 1H), 7.32-7.28 (m, 2H), 6.82-6.76 (m, 2H), 2.19 (s, 3H).

Step 2: 2-(4-Chlorophenoxy)-3-methyl-aniline

To a solution of 2-(4-chlorophenoxy)-1-methyl-3-nitro-benzene (770 mg,2.77 mmol, 1 eq) in EtOH (15 mL) and H₂O (7.5 mL) was added Fe (774.64mg, 13.87 mmol, 5 eq) and NH₄Cl (1.48 g, 27.74 mmol, 10 eq). The mixturewas stirred at 90° C. for 3 h. The reaction mixture was filtered andconcentrated under reduced pressure to yield a residue. To the residuewas added water (30 mL) and extracted with ethyl acetate (30 mL×3). Thecombined organic phase was washed with brine (20 mL), dried withanhydrous Na₂SO₄, filtered and concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=200/1 to 5/1,TLC: PE/EtOAc=5/1, R_(f)=0.50) to yield2-(4-chlorophenoxy)-3-methyl-aniline (640 mg, 2.73 mmol, 98.4% yield,99.7% purity) as colorless oil. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.27-7.21(m, 2H), 6.92 (t, J=7.8 Hz, 1H), 6.83-6.78 (m, 2H), 6.72 (dd, J=1.1, 7.9Hz, 1H), 6.59 (dd, J=0.7, 7.6 Hz, 1H), 2.02 (s, 3H); ES-LCMS m/z 234.0,236.0 [M+H]⁺.

Step 3: N-[2-(4-Chlorophenoxy)-3-methyl-phenyl]prop-2-enamide

To a solution of 2-(4-chlorophenoxy)-3-methyl-aniline (300 mg, 1.28mmol, 1 eq) in THF (10 mL) was added DIEA (497.74 mg, 3.85 mmol, 670.81μL, 3 eq) and prop-2-enoyl chloride (232.38 mg, 2.57 mmol, 209.35 μL, 2eq). The mixture was stirred at 25° C. for 1 h. The reaction mixture wasconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5μm; mobile phase: [water (0.04% NH3-H₂O+10 mM NH₄HCO₃)-ACN]; B %:50%-65%, 14 min), followed by lyophilization to yieldN-[2-(4-chlorophenoxy)-3-methyl-phenyl]prop-2-enamide (95.34 mg, 331.34μmol, 25.8% yield, 100% purity) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 7.79 (d, J=7.8 Hz, 1H), 7.28-7.13 (m, 4H), 6.79-6.74 (m,2H), 6.37-6.20 (m, 2H), 5.67 (dd, J=2.0, 9.8 Hz, 1H), 2.13 (s, 3H);ES-LCMS m/z 288.0, 290.0 [M+H]⁺.

P-16

Step 1:4-Bromo-2-(2-methyltetrazol-5-yl)-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of4-bromo-2-(2H-tetrazol-5-yl)-N-[3-(trifluoromethyl)phenyl]aniline (450mg, 1.05 mmol, 1 eq) in ACN (10 mL) was added K₂CO₃ (291.41 mg, 2.11mmol, 2 eq) and Mel (224.46 mg, 1.58 mmol, 98.45 μL, 1.5 eq). Themixture was stirred at 20° C. for 2 h. TLC (PE/EtOAc=3/1, R_(f)=0.45)showed starting material was consumed and one major new spot wasdetected. The reaction mixture was concentrated to yield a residue whichwas added H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combineorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby flash silica gel chromatography (from pure PE to PE/EtOAc=3/1, TLC:PE/EtOAc=3/1, R_(f)=0.45) to yield4-bromo-2-(2-methyltetrazol-5-yl)-N-[3-(trifluoromethyl)phenyl]aniline(230 mg, 573.79 μmol, 54.4% yield, 99.3% purity) as a white solid. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.69 (br s, 1H), 8.10 (br s, 1H), 7.59 (d,J=8.9 Hz, 1H), 7.54-7.48 (m, 1H), 7.47-7.41 (m, 2H), 7.36 (d, J=8.7 Hz,1H), 7.28 (d, J=7.3 Hz, 1H), 4.45 (s, 3H); ES-LCMS m/z 399.4 [M+H]⁺.

I-9

Step 1: 3-(3-(Trifluoromethyl)phenoxy)phenol

To a solution of 1-iodo-3-(trifluoromethyl)benzene (0.8 g, 2.94 mmol,423.28 μL, 1 eq) in DMSO (20 mL) was added K₃PO₄ (1.25 g, 5.88 mmol, 2.0eq) and benzene-1,3-diol (340.04 mg, 3.09 mmol, 515.21 μL, 1.05 eq), CuI(28.01 mg, 147.06 μmol, 0.05 eq) and 2-picolinic acid (36.21 mg, 294.11μmol, 0.1 eq). The mixture was stirred at 120° C. for 16 h. TLC(PE/EtOAc=10/1, R_(f)=0.2) showed the reaction was completed. Water (20mL) was added, the mixture was extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to yield a crude material which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 5/1,TLC: PE/EtOAc=10/1, R_(f)=0.2) to yield3-[3-(trifluoromethyl)phenoxy]phenol (500 mg, 1.77 mmol, 60.2% yield,90.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.42 (t,J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.24-7.15 (m, 3H), 6.62-6.56 (m,2H), 6.52 (s, 1H), 4.99 (s, 1H); ES-LCMS m/z 296.1 [M+MeCN+H]⁺.

Step 2: 1-(3-Fluorosulfonyloxyphenoxy)-3-(trifluoromethyl)benzene

To a solution of 3-[3-(trifluoromethyl)phenoxy]phenol (300 mg, 1.06mmol, 1 eq) in DCM (10 mL) was added DIEA (273.99 mg, 2.12 mmol, 369.26μL, 2.0 eq). The mixture was stirred under sulfuryl fluoride (30 psi) at20° C. for 16 h. TLC (PE/EtOAc=100/1, R_(f)=0.3) showed the reaction wascompleted. The mixture was concentrated and then water (10 mL) wasadded. The mixture was extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to yield a crude material which was purifiedby flash silica gel chromatography (from pure PE to PE/EtOAc 100/1, TLC:PE/EtOAc=100/1, R_(f)=0.3) to yield1-(3-fluorosulfonyloxyphenoxy)-3-(trifluoromethyl)benzene (79.86 mg,236.31 μmol, 22.3% yield, 99.5% purity) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.54-7.45 (m, 3H), 7.32 (s, 1H), 7.25-7.23 (m, 1H),7.15-7.13 (m, 1H), 7.07-7.02 (m, 2H); ES-LCMS m/z 334.87 [M−H]⁻.

I-18 & I-19

Step 1: 3-Bromo-4-fluoro-N-methyl-benzenesulfonamide

To a stirred solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (1.5g, 5.48 mmol, 1 eq) in THE (20 mL) was added methanamine/EtOH (1.03 g,10.97 mmol, 1.5 mL, 33% purity, 2 eq). The reaction mixture was stirredat 25° C. for 5 min TLC (PE/EtOAc=3/1, R_(f)=0.35) showed startingmaterial was remained and one new spot was detected. The reactionmixture was concentrated to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 3/1, TLC:PE/EtOAc=3/1, R_(f)=0.35) to yield3-bromo-4-fluoro-N-methyl-benzenesulfonamide (1.3 g, 4.61 mmol, 84.0%yield, 95.0% purity) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δ ppm8.10 (dd, J=2.3, 6.3 Hz, 1H), 7.83-7.80 (m, 8.7 Hz, 1H), 7.29-7.25 (m,1H), 4.48 (d, J=4.6 Hz, 1H), 2.70 (d, J=5.3 Hz, 3H).

Step 2: 3-Bromo-4-(cyclohexylamino)-N-methyl-benzenesulfonamide

To a stirred solution of 3-bromo-4-fluoro-N-methyl-benzenesulfonamide(500 mg, 1.77 mmol, 1 eq) in DMSO (15 mL) was added cyclohexanamine(439.27 mg, 4.43 mmol, 506.94 μL, 2.5 eq). The reaction mixture wasstirred at 140° C. for 2 h. The reaction mixture was diluted with water(100 mL), extracted with EtOAc (50 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.45) to yield3-bromo-4-(cyclohexylamino)-N-methyl-benzenesulfonamide (600 mg, 1.64mmol, 92.6% yield, 95.0% purity) as yellow oil. ¹H NMR (500 MHz, CDCl₃)δ ppm 7.90 (d, J=2.3 Hz, 1H), 7.62 (dd, J=2.0, 8.7 Hz, 1H), 6.64 (d,J=8.9 Hz, 1H), 4.77 (d, J=7.5 Hz, 1H), 4.18 (q, J=5.5 Hz, 1H), 3.44-3.33(m, 1H), 2.65 (d, J=5.5 Hz, 3H), 2.07-2.04 (m, 2H), 1.80 (td, J=3.9,13.3 Hz, 2H), 1.68 (td, J=3.8, 12.7 Hz, 1H), 1.46-1.38 (m, 2H),1.36-1.28 (m, 3H); ES-LCMS m/z 347.0, 348.9 [M+H]⁺.

Step 3: 4-(Cyclohexylamino)-N-methyl-3-vinyl-benzenesulfonamide

To a stirred solution of3-bromo-4-(cyclohexylamino)-N-methyl-benzenesulfonamide (550 mg, 1.50mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (278.07mg, 1.81 mmol, 306.25 μL, 1.2 eq) in water (3 mL) and 1,4-dioxane (9 mL)was added Cs₂CO₃ (1.47 g, 4.51 mmol, 3 eq) and Pd(dppf)Cl₂ (110.09 mg,150.46 μmol, 0.1 eq). The reaction mixture was bubbled with N₂ for 3 minthen stirred at 100° C. for 30 min under microwave. The reaction mixturewas filtered through a pad of celite and the filtrate was concentratedto yield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.40) to yield4-(cyclohexylamino)-N-methyl-3-vinyl-benzenesulfonamide (450 mg, 1.50mmol, 99.5% yield, 97.9% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃)δ ppm 7.66 (t, J=2.6 Hz, 1H), 7.63-7.58 (m, 1H), 6.67-6.59 (m, 2H),5.71-5.63 (m, 1H), 5.46-5.40 (m, 1H), 4.27-4.15 (m, 2H), 3.37 (d, J=3.4Hz, 1H), 2.64 (dd, J=3.3, 5.5 Hz, 3H), 2.09-2.05 (m, 2H), 1.78 (dd,J=3.3, 13.3 Hz, 2H), 1.68 (dd, J=3.5, 9.2 Hz, 1H), 1.45-1.36 (m, 2H),1.29-1.26 (m, 3H); ES-LCMS m/z 295.0 [M+H]⁺.

Step 4:3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-4-(cyclohexylamino)-N-methyl-benzenesulfonamide&3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-4-(cyclohexylamino)-N-methyl-benzenesulfonamide

To a stirred solution of4-(cyclohexylamino)-N-methyl-3-vinyl-benzenesulfonamide (440 mg, 1.46mmol, 1 eq) and dibromomethanone oxime (445.15 mg, 2.19 mmol, 1.5 eq) inEtOAc (30 mL) was added NaHCO₃ (1.23 g, 14.63 mmol, 10 eq). The reactionmixture was stirred at 25° C. for 2 h. The reaction mixture was washedwith water (30 mL×2). The organic layer was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.50) to yield a residuewhich was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm,Sum); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 40%-40%, min), followed bylyophilization to yield3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-4-(cyclohexylamino)-N-methyl-benzenesulfonamide(104.74 mg, 246.04 μmol, 16.8% yield, 97.8% purity, SFC: R_(t)=5.614min, ee=99.9%, [α]^(24.0) _(D)=+63.6, MeOH, c=0.107 g/100 mL) as whitesolid; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.70 (dd, J=2.0, 8.8 Hz, 1H), 7.55(d, J=2.2 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 5.67 (t, J=11.2 Hz, 1H), 4.66(d, J=6.8 Hz, 1H), 4.20 (q, J=5.1 Hz, 1H), 3.61-3.34 (m, 3H), 2.64 (d,J=5.4 Hz, 3H), 2.01 (s, 2H), 1.75 (dd, J=4.3, 8.9 Hz, 2H), 1.69-1.60 (m,1H), 1.49-1.38 (m, 2H), 1.36-1.26 (m, 3H); ES-LCMS m/z 416.0, 418.0[M+H]⁺ and3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-4-(cyclohexylamino)-N-methyl-benzenesulfonamide(99.78 mg, 236.55 μmol, 16.2% yield, 98.7% purity, SFC: R_(t)=5.904 min,ee=98.1%, [α]^(24.0) _(D)=−69.4, MeOH, c=0.098 g/100 mL) as white solid;¹H NMR (400 MHz, CDCl₃) δ ppm 7.70 (dd, J=2.1, 8.7 Hz, 1H), 7.55 (d,J=2.2 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 5.67 (t, J=11.2 Hz, 1H), 4.66 (d,J=7.1 Hz, 1H), 4.19 (q, J=5.4 Hz, 1H), 3.57-3.38 (m, 3H), 2.64 (d, J=5.6Hz, 3H), 2.01 (s, 2H), 1.75 (dd, J=4.2, 8.8 Hz, 2H), 1.68-1.61 (m, 1H),1.48-1.38 (m, 2H), 1.37-1.26 (m, 3H); ES-LCMS m/z 416.0, 417.9 [M+H]⁺.

I-20 & I-21

Step 1: 2-Bromo-N-[3-(trifluoromethyl)phenyl]aniline

To a mixture of 2-bromoaniline (2 g, 11.63 mmol, 1 eq),[3-(trifluoromethyl)phenyl]boronic acid (2.21 g, 11.63 mmol, 1 eq) andCu(OAc)₂ (2.11 g, 11.63 mmol, 1 eq) in DCM (20 mL) was added DIEA (2.25g, 17.44 mmol, 3.04 mL, 1.5 eq). The mixture was stirred under O₂atmosphere at 20° C. for 17 h. TLC (PE/EA=3/1, R_(f)=0.5) showedstarting material disappeared. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (from pure PE toPE/EtOAc=3/1) to yield 2-bromo-N-[3-(trifluoromethyl)phenyl]aniline (2.4g, 6.07 mmol, 52.2% yield, 80.0% purity) as light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.55 (dd, J=1.5, 7.8 Hz, 1H), 7.42-7.36 (m, 1H),7.34 (s, 1H), 7.29-7.21 (m, 4H), 6.86-6.78 (m, 1H), 6.13 (br s, 1H);ES-LCMS m/z 316.0, 318.0 [M+H]⁺.

Step 2: N-[3-(Trifluoromethyl)phenyl]-2-vinyl-aniline

To a mixture of 2-bromo-N-[3-(trifluoromethyl)phenyl]aniline (2.2 g,5.57 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.29g, 8.35 mmol, 1.42 mL, 1.5 eq) and Pd(dppf)Cl₂ (203.69 mg, 278.38 μmol,0.05 eq) in 1,4-dioxane (8 mL) was added Cs₂CO₃ (2 M, 5.57 mL, 2 eq).The mixture was stirred under N₂ atmosphere at 100° C. for 0.5 h inmicrowave. TLC (PE/EA=10/1, R_(f)=0.6) showed starting materialdisappeared. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was diluted with H₂O (20 mL) andextracted with EtOAc (20 mL×2). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (pure PE) to yieldN-[3-(trifluoromethyl)phenyl]-2-vinyl-aniline (570 mg, 1.95 mmol, 35.0%yield, 90.0% purity) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm7.54 (d, J=7.8 Hz, 1H), 7.34-7.28 (m, 1H), 7.27-7.22 (m, 2H), 7.16-7.07(m, 3H), 7.02 (d, J=7.0 Hz, 1H), 6.86 (dd, J=11.0, 17.6 Hz, 1H), 5.72(dd, J=1.4, 17.4 Hz, 1H), 5.64 (br s, 1H), 5.33 (dd, J=1.4, 11.2 Hz,1H); ES-LCMS m/z 264.0 [M+H]⁺.

Step 3:2-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-N-[3-(trifluoromethyl)phenyl]anilineand2-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-[3-(trifluoromethyl)phenyl]aniline

To a mixture ofN-[3-(trifluoromethyl)phenyl]-2-vinyl-aniline (500.19 mg,1.71 mmol, 1 eq) in EtOAc (10 mL) was added dibromomethanone oxime(416.21 mg, 2.05 mmol, 1.2 eq) and NaHCO₃ (287.19 mg, 3.42 mmol, 2.0eq). The mixture was stirred at 20° C. for 4 h. TLC (PE/EtOAc=3/1,R_(f)=0.5) indicated Reactant 1 was consumed completely and one new spotformed. The reaction mixture was diluted with water (10 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a crude material which was purified on silicagel column chromatography (from PE/EtOAc=100/1 to 3/1, TLC(PE/EtOAc=3/1, R_(f)=0.5). The desired fraction was concentrated underreduced pressure to yield a reside which was separated by chiral SFC(column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [0.1%NH₃.H₂O/EtOH]; B %: 20%-20%) to yield peak 1 and peak 2. Peak 1 wasconcentrated under reduced pressure to yield a residue which waslyophilized to yield2-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-[3-(trifluoromethyl)phenyl]aniline(28.52 mg, 74.04 μmol, 4.3% yield, 100.0% purity, SFC: R_(t)=2.28,ee=99.9%, [α]^(24.2) _(D)=−19.2 (EtOH, c=0.104 g/100 mL) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.48 (d, J=12.0 Hz, 1H), 7.45-7.18(m, 4H), 7.00-6.95 (m, 3H), 5.88-5.83 (m, 1H), 3.63 (q, J=10.8 Hz, 1H),3.06 (q, J=8.8 Hz, 1H); ES-LCMS m z 384.9, 386.9 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which waslyophilized to yield2-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-[3-(trifluoromethyl)phenyl]aniline(26.28 mg, 68.23 μmol, 4.0% yield, 100.0% purity, SFC: R_(t)=2.579,ee=99.5% and [α]^(24.2) _(D)=9.3 (EtOH, c=0.108 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.46 (d, J=16.0 Hz, 1H), 7.32-7.18(m, 4H), 7.00-6.95 (m, 3H), 5.88-5.83 (m, 1H), 3.65 (q, J=12.0 Hz, 1H),3.08 (q, J=12.0 Hz, 1H); ES-LCMS m/z 384.9, 386.9 [M+H]⁺.

I-13

Step 1: 2-Amino-5-bromo-N-methoxy-N-methyl-benzamide

To a solution of 2-amino-5-bromo-benzoic acid (3.5 g, 16.20 mmol, 1 eq)in DMF (50 mL) was added N-methoxymethanamine (4.74 g, 48.60 mmol, 3 eq,HCl), HATU (7.39 g, 19.44 mmol, 1.2 eq) and TEA (4.92 g, 48.60 mmol,6.77 mL, 3 eq). The mixture was stirred at 15° C. for 12 h. TLC(PE/EtOAc=1/1, R_(f)=0.39) indicated the starting material was consumedcompletely and one new spot formed. The reaction mixture was quenched byaddition of water (200 mL) and extracted with EtOAc (200 mL×3). Thecombined organic layers were washed with brine (200 mL), dried overNa₂SO₄, concentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from pure PE toPE/EtOAc=2/1) to yield 2-amino-5-bromo-N-methoxy-N-methyl-benzamide (3.5g, 12.89 mmol, 79.5% yield, 95.4% purity) as a yellow solid. ¹H NMR (400MHz, CD₃OD) δ ppm 7.37 (d, J=2.3 Hz, 1H), 7.26 (dd, J=2.3, 9.0 Hz, 1H),6.71 (d, J=8.6 Hz, 1H), 3.60 (s, 3H), 3.32 (s, 3H); ES-LCMS m/z 258.9,260.9 [M+H]⁺.

Step 2:5-Bromo-N-methoxy-N-methyl-2-[3-(trifluoromethyl)anilino]benzamide

A mixture of 2-amino-5-bromo-N-methoxy-N-methyl-benzamide (3.5 g, 12.89mmol, 1 eq), 1-iodo-3-(trifluoromethyl)benzene (5.26 g, 19.33 mmol, 2.78mL, 1.5 eq), Cs₂CO₃ (8.40 g, 25.77 mmol, 2 eq), XPhos (614.35 mg, 1.29mmol, 0.1 eq) and Pd(OAc)₂ (144.66 mg, 644.35 μmol, 0.05 eq) in1,4-dioxane (200 mL) was degassed and purged with N₂ for 3 times and themixture was stirred under N₂ atmosphere at 90° C. for 12 h. The reactionmixture was quenched by addition of water (300 mL) and extracted withEtOAc (300 mL×3). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 5/1, TLC:PE/EtOAc=3/1, R_(f)=0.60)to yield5-bromo-N-methoxy-N-methyl-2-[3-(trifluoromethyl)anilino]benzamide (1 g,2.29 mmol, 17.8% yield, 92.3% purity) as a yellow oil. H NMR (400 MHz,DMSO-d₆) δ ppm 8.13 (s, 1H), 7.57-7.52 (m, 2H), 7.43-7.37 (m, 1H),7.27-7.20 (m, 3H), 7.12 (d, J=7.7 Hz, 1H), 3.47 (s, 3H), 3.19-3.14 (m,3H); ES-LCMS m/z 402.9, 404.9 [M+H]⁺.

Step 3: 1-[5-Bromo-2-[3-(trifluoromethyl)anilino]phenyl]ethanone

To a solution of5-bromo-N-methoxy-N-methyl-2-[3-(trifluoromethyl)anilino]benzamide (700mg, 1.60 mmol, 1 eq) in THE (10 mL) was added MeMgBr (3 M, 4.27 mL, 8eq) at −70° C. under N₂ atmosphere. After being stirred for 1 h, themixture was stirred at 0° C. for 1 h. TLC (PE/EtOAc=10/1, R_(f)=0.85)indicated starting material was consumed completely and one new spotformed. The reaction mixture was quenched by addition of water (50 mL)and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (40 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=1/0 to 20/1, TLC:PE/EtOAc=10/1, R_(f)=0.85) to yield1-[5-bromo-2-[3-(trifluoromethyl)anilino]phenyl]ethanone (450 mg, 1.26mmol, 78.4% yield, 100.0% purity) as a yellow solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 8.06 (d, J=2.3 Hz, 1H), 7.57-7.45 (m, 4H), 7.38 (d, J=7.8Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 2.63 (s, 3H); ES-LCMS m/z 357.9, 359.9[M+H]⁺.

Step 4:1-[5-Bromo-2-[3-(trifluoromethyl)anilino]phenyl]-2-chloro-ethanone

To a solution of1-[5-bromo-2-[3-(trifluoromethyl)anilino]phenyl]ethanone (300 mg, 837.63μmol, 1 eq) in DCM (10 mL) was added dropwise DIEA (324.77 mg, 2.51mmol, 437.70 μL, 3 eq) and TMSOTf (558.52 mg, 2.51 mmol, 454.08 μL, 3eq) at 0° C. After addition, the mixture was stirred at 25° C. for 2 hand then NCS (167.77 mg, 1.26 mmol, 1.5 eq) was added. The resultingmixture was stirred at 25° C. for 2 h. TLC (PE/EtOAc=10/1, R_(f)=0.78)indicated starting material was consumed completely and one new spotformed. The reaction mixture was quenched by addition of water (50 mL)and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from pure PE to PE/EtOAc=25/1, TLC:PE/EtOAc=10/1, R_(f)=0.78) to yield1-[5-bromo-2-[3-(trifluoromethyl)anilino]phenyl]-2-chloro-ethanone (180mg, 443.78 μmol, 52.9% yield, 96.8% purity) as a yellow solid. ¹H NMR(400 MHz, CD₃OD) δ ppm 8.05 (d, J=2.3 Hz, 1H), 7.62-7.47 (m, 4H), 7.42(d, J=7.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 4.90 (s, 2H); ES-LCMS m/z391.9, 393.9, 395.9 [M+H]⁺.

I-23 & I-24

Step 1: 4-Bromo-2-(4-chlorophenoxy)-1-methylbenzene

To a solution of 1-chloro-4-iodo-benzene (6 g, 25.16 mmol, 1 eq) in DMSO(100 mL) was added K₃PO₄ (10.68 g, 50.32 mmol, 2.0 eq) and5-bromo-2-methyl-phenol (5.18 g, 27.68 mmol, 1.1 eq), CuI (239.61 mg,1.26 mmol, 0.05 eq) and 2-Picolinic acid (309.77 mg, 2.52 mmol, 0.1 eq).The mixture was stirred at 120° C. for 16 h. TLC (PE/EtOAc=100/1,R_(f)=0.5) showed the reaction was completed. To the mixture was addedwater (100 mL). The mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to yield a crude material which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 100/1,TLC: PE/EtOAc=100/1, R_(f)=0.6) to yield4-bromo-2-(4-chlorophenoxy)-1-methyl-benzene (7 g, 21.17 mmol, 84.1%yield, 90.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm7.29-7.28 (m, 2H), 7.27 (s, 1H), 7.26-7.25 (m, 1H), 7.21-6.98 (m, 1H),6.99-6.88 (m, 2H), 2.18 (s, 3H).

Step 2: 2-(4-Chlorophenoxy)-1-methyl-4-vinylbenzen

To a mixture of 4-bromo-2-(4-chlorophenoxy)-1-methyl-benzene (3 g, 9.07mmol, 1 eq) in DMF (20 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.68 g, 10.89 mmol,1.85 mL, 1.2 eq), cyclopentyl(diphenyl)phosphane; dichloropalladium;iron (663.90 mg, 907.34 μmol, 0.1 eq) and Cs₂CO₃ (5.91 g, 18.15 mmol,2.0 eq). The mixture was stirred under N₂ atmosphere at 100° C. for 4 h.TLC (PE/EtOAc=3/1, R_(f)=0.5) showed the reaction was completed. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was diluted with H₂O (20 mL) and extracted withEtOAc (20 mL×2). The combined organic layers were washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto yield a residue which was purified by flash silica gel chromatography(from pure PE to PE/EtOAc=3/1, TLC: PE/EtOAc=3/1, R_(f)=0.5) to yield2-(4-chloropenoxy)-1-methyl-4-vinyl-benzene (1.5 g, 5.52 mmol, 60.8%yield, 90.0% purity) as yellow oil. ¹H NMR (400 MHz, CD₃OD) δ ppm7.31-7.24 (m, 3H), 7.20-7.19 (m, 1H), 6.97-6.88 (m, 1H), 6.86-6.84 (m,2H), 6.64 (s, 1H), 5.67 (d, J=8.0 Hz, 1H), 5.17 (d, J=8.0 Hz, 1H), 2.17(s, 3H).

Step 3:(R)—3-Bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazoleand(S)-3-bromo-5-(3-(4-chlorophenoxy)-4-methylphenyl)-4,5-dihydroisoxazole

To a mixture of 2-(4-chlorophenoxy)-1-methyl-4-vinyl-benzene (500 mg,1.84 mmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (1.54 g, 18.40 mmol,10 eq) and dibromomethanone oxime (447.86 mg, 2.21 mmol, 1.2 eq). Themixture was stirred at 20° C. for 4 h. TLC (PE/EtOAc=3/1, R_(f)=0.5)indicated Reactant 1 was consumed completely and one new spot formed.The reaction mixture was diluted with water (10 mL) and extracted withEtOAc (10 mL×3). The combined organic layers were washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto yield a crude material which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 3/1, TLC PE/EtOAc=3/1,R_(f)=0.5). The desired fraction was concentrated under reduced pressureto yield a reside which was separated by chiral SFC (column: DAICELCHIRALPAK AS-H (250 mm*30 mm, Sum); mobile phase: [0.1% NH₃.H₂O/EtOH]; B%: 25%-25%) to yield peak 1 and peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was lyophilized to yield(5R)-3-bromo-5-[3-(4-chlorophenoxy)-4-methyl-phenyl]-4,5-dihydroisoxazole(25.1 mg, 65.79 μmol, 3.6% yield, 96.1% purity, SFC: R_(t)=2.674,ee=98.0%, [α]^(24.2) _(D)=145 (MeOH, c=0.04 g/100 mL) as a white solid.¹H NMR (400 MHz, CD₃OD) δ ppm 7.34-7.32 (m, 3H), 7.25-7.23 (m, 1H),6.90-6.85 (m, 3H), 5.65-5.60 (m, 1H), 3.63 (q, J=11.8 Hz, 1H), 3.17 (q,J=9.8 Hz, 1H), 2.20 (s, 3H); ES-LCMS m z 365.9, 367.9 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which waslyophilized to yield(5S)-3-bromo-5-[3-(4-chlorophenoxy)-4-methyl-phenyl]-4,5-dihydroisoxazole(23.28 mg, 62.35 μmol, 3.4% yield, 98.2% purity, SFC: R_(t)=2.674,ee=98.6%, [α]^(24.2) _(D)=−185 (MeOH, c=0.04 g/100 mL) as a white solid.¹H NMR (400 MHz, CD₃OD) δ ppm 7.32-7.29 (m, 3H), 7.25-7.24 (m, 1H),6.89-6.84 (m, 3H), 5.64-5.59 (m, 1H), 3.62 (q, J=11.8 Hz, 1H), 3.16 (q,J=9.8 Hz, 1H), 2.19 (s, 3H); ES-LCMS m/z 365.9, 367.9 [M+H]⁺.

I-5

Step 1:3-(2-Methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzenesulfonylfluoride

To a solution of4-bromo-2-(2-methyltetrazol-5-yl)-N-[3-(trifluoromethyl)phenyl]aniline(60 mg, 135.62 μmol, 1 eq) in i-PrOH (4 mL) was added1,4-diazoniabicyclo[2.2.2]octane-1,4-disulfinate (97.77 mg, 406.85 μmol,3 eq), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium(28.81 mg, 40.69 μmol, 28.81 μL, 0.3 eq),N-cyclohexyl-N-methyl-cyclohexanamine (158.95 mg, 813.70 μmol, 172.59μL, 6 eq) and stirred at 110° C. in microwave (5 bar) for 1 h under N₂atmosphere. To the mixture was added NFSI (256.59 mg, 813.70 μmol, 6.00eq) and stirred at 25° C. for 11 h. The reaction was carried out for 4times in parallel. TLC (PE/EtOAc=4:1, R_(f)=0.35) showed startingmaterial was consumed completely and two major new spots were detected.The reaction mixture was concentrated, diluted with H₂O (15 mL) andextracted with EtOAc (10 mL×2). The combine organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated to yield a residuewhich was purified by preparative TLC (PE/EtOAc=4/1, TLC: PE/EtOAc=4/1,R_(f)=0.35) and then by flash silica gel chromatography (from pure PE toPE/EtOAc=8/1, TLC: PE/EtOAc=4/1, R_(f)=0.35) to yield3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzenesulfonylfluoride (48.29 mg, 120.32 μmol, 22.2% yield, 100.0% purity) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.53 (s, 1H), 8.56 (d, J=2.4 Hz,1H), 8.01 (dd, J=2.4, 9.1 Hz, 1H), 7.76-7.71 (m, 2H), 7.71-7.67 (m, 1H),7.60 (d, J=7.5 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 4.51 (s, 3H); ES-LCMSm/z 402.0 [M+H]⁺, 443.1 [M+ACN+H]⁺.

I-29

Step 1: tert-Butyl N-(4-hydroxy-2-naphthyl)carbamate

To a solution of 4-hydroxynaphthalene-2-carboxylic acid (2 g, 10.63mmol, 1 eq) in toluene (20 mL) was added DPPA (3.51 g, 12.75 mmol, 2.76mL, 1.2 eq), t-BuOH (3.94 g, 53.14 mmol, 5.08 mL, 5 eq) and TEA (2.15 g,21.26 mmol, 2.96 mL, 2 eq) under N₂. The mixture was stirred at 90° C.for 12 h. The reaction mixture was quenched by addition of sat. aq.NaHCO₃ (100 mL), extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 5/1,TLC: PE/EtOAc=5/1, R_(f)=0.72) to yield tert-butylN-(4-hydroxy-2-naphthyl)carbamate (1.0 g, 2.31 mmol, 21.7% yield, 60.0%purity) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.07 (d, J=8.2Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.45-7.40 (m, 1H), 7.33 (d, J=7.0 Hz,2H), 7.26-7.21 (m, 1H), 7.09 (s, 1H), 6.59 (br s, 1H), 1.55 (s, 9H);ES-LCMS m/z 260.0 [M+H]⁺.

Step 2: tert-ButylN-[4-[3-(trifluoromethyl)phenoxy]-2-naphthyl]carbamate

A mixture of tert-butyl N-(4-hydroxy-2-naphthyl)carbamate (700 mg, 1.62mmol, 1 eq), 1-iodo-3-(trifluoromethyl)benzene (352.46 mg, 1.30 mmol,186.49 μL, 0.8 eq), 2-Picolinic acid (19.94 mg, 161.97 μmol, 0.1 eq),K₃PO₄ (687.65 mg, 3.24 mmol, 2 eq) and CuI (15.42 mg, 80.99 μmol, 0.05eq) in DMSO (30 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 120° C. for 12 h under N₂ atmosphere.The reaction mixture was quenched by addition of water (100 mL),extracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=1/0 to 10/1, TLC: PE/EtOAc=5/1,R_(f)=0.72) to yield tert-butylN-[4-[3-(trifluoromethyl)phenoxy]-2-naphthyl]carbamate (150 mg, 167.33μmol, 10.3% yield, 45.0% purity) as brown oil. ES-LCMS m/z 404.0 [M+H]⁺.

Step 3: 4-[3-(Trifluoromethyl)phenoxy]naphthalen-2-amine

To a solution of tert-butylN-[4-[3-(trifluoromethyl)phenoxy]-2-naphthyl]carbamate (150 mg, 173.28μmol, 1 eq) in DCM (5 mL) was added TFA (2.31 g, 20.26 mmol, 1.5 mL,116.92 eq). The mixture was stirred at 20° C. for 2 h. The reactionmixture was concentrated to yield4-[3-(trifluoromethyl)phenoxy]naphthalen-2-amine (78 mg, 117.76 μmol,67.9% yield, 63.0% purity, TFA) as brown oil, which was used in the nextstep without further purification, ES-LCMS m z 304.0 [M+H]⁺.

Step 4: N-[4-[3-(Trifluoromethyl)phenoxy]-2-naphthyl]prop-2-enamide

To a solution of 4-[3-(trifluoromethyl)phenoxy]naphthalen-2-amine (78mg, 117.76 μmol, 1 eq, TFA) and TEA (119.16 mg, 1.18 mmol, 163.90 μL, 10eq) in THE (5 mL) was added prop-2-enoyl chloride (21.32 mg, 235.51μmol, 19.20 μL, 2 eq). The mixture was stirred at 20° C. for 2 h. Thereaction mixture was concentrated to yield a residue which was purifiedby preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 53%-83%, 10 min), followed bylyophilization to yieldN-[4-[3-(trifluoromethyl)phenoxy]-2-naphthyl]prop-2-enamide (19.39 mg,54.26 μmol, 46.0% yield, 100% purity) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.34 (s, 1H), 8.25 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.92(d, J=8.3 Hz, 1H), 7.71-7.64 (m, 1H), 7.60-7.54 (m, 2H), 7.53-7.43 (m,2H), 7.39 (d, J=8.1 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 6.47-6.36 (m, 1H),6.32-6.23 (m, 1H), 5.83-5.73 (m, 1H); ES-LCMS m/z 358.0 [M+H]⁺.

I-25 & I-26

Step 1: 4-Acetamido-3-bromobenzenesulfonyl Chloride

Chlorosulfonic acid (13.470 g, 115.60 mmol, 7.70 mL, 4.95 eq) was addedinto N-(2-bromophenyl)acetamide (5. g, 23.36 mmol, 1 eq) at 0° C. Themixture was stirred at 80° C. for 4 h. TLC (PE/EtOAc=3/1, R_(f)=0.5)indicated starting material was consumed completely and one new spotformed. The reaction mixture was quenched by addition ice water (50 mL)at 0° C., then diluted with H₂O (20 mL) and extracted with EtOAc (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield4-acetamido-3-bromo-benzenesulfonyl chloride (4.5 g, crude) as yellowoil, which was used in the next step without further purification.

Step 2: N-(2-Bromo-4-(N-methylsulfamoyl)phenyl)acetamide

To a solution of 4-acetamido-3-bromo-benzenesulfonyl chloride (4.5 g,14.40 mmol, 1 eq) in DCM (40 mL) was added MeNH₂/EtOH (2.71 g, 28.79mmol, 14.40 mL, 33% purity, 2.0 eq) at 0° C. The mixture was stirred at20° C. for 4 h. TLC (PE/EtOAc=3:1, R_(f)=0.1) showed the reaction wascompleted. The mixture was concentrated and then water (20 mL) wasadded. The mixture was extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated to yieldN-[2-bromo-4-(methylsulfamoyl)phenyl]acetamide (3.3 g, 9.67 mmol, 67.2%yield, 90.0% purity) as a yellow solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.66 (s,1H), 7.99-7.93 (m, 2H), 7.75 (dd, J=2.0, 8.5 Hz, 1H), 7.55 (q, J=4.9 Hz,1H), 2.44 (d, J=4.9 Hz, 3H), 2.15 (s, 3H).

Step 3: 4-Amino-3-bromo-N-methylbenzenesulfonamide

To a solution ofN-[2-bromo-4-(methylsulfamoyl)phenyl]acetamide (3.0 g,8.79 mmol, 1 eq) in HCl (20 mL) was added H₂O (20 mL). The mixture wasstirred at 100° C. for 16 h. TLC (PE/EtOAc=3:1, R_(f)=0.1) showed thereaction was completed. The mixture was concentrated and then water (20mL) was added. The mixture was extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to yield4-amino-3-bromo-N-methyl-benzenesulfonamide (2.5 g, 8.49 mmol, 96.6%yield, 90.0% purity) as yellow solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.68 (d,J=4.9 Hz, 1H), 7.43 (dd, J=1.8, 8.5 Hz, 1H), 7.12 (q, J=4.9 Hz, 1H),6.86 (q, J=8.5 Hz, 1H), 6.15 (s, 2H), 2.36 (d, J=5.0 Hz, 3H).

Step 4:3-Bromo-N-methyl-4-((3-(trifluoromethyl)phenyl)amino)benzenesulfonamide

To a mixture of 4-amino-3-bromo-N-methyl-benzenesulfonamide (2.5 g, 8.49mmol, 1 eq) in DCM (20 mL) was added [3-(trifluoromethyl)phenyl]boronicacid (2.42 g, 12.73 mmol, 1.5 eq) and Cu(OAc)₂ (1.85 g, 10.18 mmol, 1.2eq), DIEA (3.29 g, 25.46 mmol, 4.43 mL, 3.0 eq). The mixture was stirredunder 02 (30 psi) at 20° C. for 16 h. TLC (PE/EtOAc=3/1, R_(f)=0.3)showed the reaction was completed. The mixture was concentrated anddiluted with water (20 mL). The mixture was extracted with DCM (20mL×3). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to yield the residue to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=20/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.3) to yield3-bromo-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide (1.5g, 3.30 mmol, 38.9% yield, 90.0% purity) as yellow oil. ¹H NMR (400 MHz,CD₃OD) δ ppm 7.96 (d, J=2.0 Hz, 1H), 7.62-7.60 (m, 2H), 7.24-7.22 (m,1H), 7.13-7.12 (m, 1H), 6.77-6.75 (m, 1H), 2.52 (q, J=10.8 Hz, 1H), 2.51(q, J=2.4 Hz, 3H); ES-LCMS m/z 408.9, 410.9 [M+H]⁺.

Step 4:N-Methyl-4-((3-(trifluoromethyl)phenyl)amino)-3-vinylbenzenesulfonamide

To a solution of3-bromo-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide (400mg, 918.82 μmol, 1 eq) in DMF (20 mL) was added Cs₂CO₃ (598.74 mg, 1.84mmol, 2.0 eq), Pd(dppf)Cl₂ (67.23 mg, 91.88 μmol, 0.1 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (141.51 mg, 918.82 μmol,155.85 μL, 1 eq). The mixture was stirred under N2 at 100° C. for 4 h.TLC (PE/EtOAc=10/1, R_(f)=0.5) showed the reaction was completed. Themixture was added water (20 mL), extracted with EtOAc (40 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=100/1 to 5/1, TLC:PE/EtOAc=5/1, R_(f)=0.5) to yieldN-methyl-4-[3-(trifluoromethyl)anilino]-3-vinyl-benzenesulfonamide (300mg, 673.47 μmol, 73.3% yield, 80.0% purity) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 7.61-7.43 (m, 6H), 7.20-7.19 (m, 1H), 6.72-6.70 (m,1H), 5.80 (d, J=20.0 Hz, 1H), 5.53 (d, J=12.0 Hz, 1H), 3.16 (q, J=4.0Hz, 3H); ES-LCMS m/z 357.0 [M+H]⁺.

Step 5:(R)—3-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-4-((3-(trifluoromethyl)phenyl)amino)benzenesulfonamideand(S)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-4-((3-(trifluoromethyl)phenyl)amino)benzenesulfonamide

To a mixture ofN-methyl-4-[3-(trifluoromethyl)anilino]-3-vinyl-benzenesulfonamide (250mg, 631.38 μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (530.42 mg,6.31 mmol, 10 eq) and dibromomethanone oxime (153.68 mg, 757.66 μmol,1.2 eq). The mixture was stirred at 20° C. for 4 h. The reaction mixturewas diluted with water (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC (PE/EtOAc=3/1, R_(f)=0.2). The desiredfraction was concentrated under reduced pressure to yield a reside whichwas separated by chiral SFC (column: column: DAICEL CHIRALCEL OJ-H (250mm*30 mm, 5 um); mobile phase: [0.1% NH₃.H₂O EtOH]; B %: 40%-40%) toyield peak 1 and peak 2. Peak 1 was concentrated under reduced pressureto yield a residue which was lyophilized to yield3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(13.15 mg, 27.49 μmol, 4.4% yield, 100.0% purity, SFC: R_(t)=3.304,ee=100%, [α]^(24.2) _(D)=+10 (MeOH, c=0.02 g/100 mL)) as a white solid.¹H NMR (400 MHz, CD₃OD) δ ppm 7.87 (d, J=4.0 Hz, 1H), 7.71 (d, J=8.0 Hz,1H), 7.50-7.47 (m, 1H), 7.38-7.31 (m, 3H), 7.30 (d, J=1.6 Hz, 1H), 6.00(q, J=8.0 Hz, 1H), 3.75 (q, J=4.0 Hz, 1H), 3.23-3.17 (m, 1H), 2.53 (d,J=4.2 Hz, 3H); ES-LCMS m/z 478.0, 480.0 [M+H]⁺. Peak 2 was concentratedunder reduced pressure to yield a residue which was lyophilized to yield3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(14.20 mg, 29.69 μmol, 4.7% yield, 100.0% purity, SFC: R_(t)=3.553,ee=100%, [α]^(24.2) _(D)=−50 (MeOH, c=0.02 g/100 mL) as a white solid.¹H NMR (400 MHz, CD₃OD) δ ppm 7.88 (d, J=4.0 Hz, 1H), 7.72 (d, J=8.0 Hz,1H), 7.51-7.48 (m, 1H), 7.38-7.31 (m, 3H), 7.30 (d, J=1.6 Hz, 1H), 6.01(q, J=8.0 Hz, 1H), 3.77 (q, J=4.0 Hz, 1H), 3.24-3.17 (m, 1H), 2.54 (d,J=4.2 Hz, 3H); ES-LCMS m/z 478.0, 480.0 [M+H]⁺.

I-15

Step 1: 2-(3-(Trifluoromethyl)phenoxy)benzonitrile

To a solution of 2-fluorobenzonitrile (1 g, 8.26 mmol, 877.19 μL, 1 eq)in DMF (20 mL) was added K₂CO₃ (2.28 g, 16.51 mmol, 2 eq) and3-(trifluoromethyl)phenol (1.61 g, 9.91 mmol, 1.19 mL, 1.2 eq). Themixture was stirred at 100° C. for 4 h. TLC (PE/EtOAc=100/1, R_(f)=0.2)showed the reaction was completed. Water (20 mL) was added. The mixturewas extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedto yield a residue which was purified by flash silica gel chromatography(from pure PE to PE/EtOAc=100/1, TLC: PE/EtOAc=10/1, R_(f)=0.2) to yield2-[3-(trifluoromethyl)phenoxy]benzonitrile (1 g, 3.42 mmol, 41.4% yield,90.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.81-7.79 (m,1H), 7.66-7.64 (m, 2H), 7.55 (s, 1H), 7.38-7.32 (m, 3H), 7.05-7.03 (m,1H).

Step 2: 2-(3-(Trifluoromethyl)phenoxy)benzoic Acid

To a solution of 2-[3-(trifluoromethyl)phenoxy]benzonitrile (1 g, 3.42mmol, 1 eq) in EtOH (5 mL) was added NaOH (1.03 g, 25.64 mmol, 7.5 eq)and H₂O (5 mL). The mixture was stirred at 100° C. for 16 h. TLC(PE/EtOAc=100/1, R_(f)=0.1) showed the reaction was completed. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was diluted with H₂O (20 mL) and extracted withEtOAc (20 mL×2). The combined organic layers were washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto yield 2-[3-(trifluoromethyl)phenoxy]benzoic acid (1 g, 3.19 mmol,93.3% yield, 90.0% purity) as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm 10.05 (s, 1H), 8.17-8.14 (m, 1H), 7.56-7.43 (m, 5H), 7.28-7.17 (m,1H), 6.98-6.95 (m, 1H); ES-LCMS m/z 283.1 [M+H]⁺.

Step 3: N-Methoxy-N-methyl-2-(3-(trifluoromethyl)phenoxy)benzamide

To a solution of 2-[3-(trifluoromethyl)phenoxy]benzoic acid (500 mg,1.59 mmol, 1 eq) in DCM (10 mL) was added HATU (727.55 mg, 1.91 mmol,1.2 eq) and N-methoxymethanamine; hydrochloride (186.64 mg, 1.91 mmol,1.2 eq), DIEA (618.25 mg, 4.78 mmol, 833.22 μL, 3.0 eq). The mixture wasstirred at 20° C. for 16 h. TLC (PE/EtOAc=5/1, R_(f)=0.3) showed thereaction was completed. The mixture was concentrated and then water (10mL) was added. The mixture was extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=100/1 to 5/1, TLC(PE/EtOAc=5/1, R_(f)=0.3) to yieldN-methoxy-N-methyl-2-[3-(trifluoromethyl)phenoxy]benzamide (250 mg,691.71 μmol, 43.4% yield, 90.0% purity) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.43-7.38 (m, 4H), 7.34-7.23 (m, 3H), 6.92 (s, 1H), 3.51(s, 3H), 3.26 (s, 3H); ES-LCMS m/z 326.0 [M+H]⁺.

Step 4: 1-(2-(3-(Trifluoromethyl)phenoxy)phenyl)ethan-1-one

To a mixture ofN-methoxy-N-methyl-2-[3-(trifluoromethyl)phenoxy]benzamide (200 mg,553.37 μmol, 1 eq) in THE (10 mL) was added MeMgBr (3 M, 1.84 mL, 10 eq)at 0° C. The mixture was stirred under N₂ atmosphere at 0° C. for 2 h.TLC (PE/EtOAc=5/1, R_(f)=0.4) showed the reaction was completed. Thereaction mixture was quenched by the addition of saturated aqueous NH₄Clsolution (20 mL) at 0° C. The mixture was concentrated, diluted withwater (10 mL) and extracted with EtOAc (10 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 5/1, TLC (PE/EtOAc=5/1,R_(f)=0.4) to yield 1-[2-[3-(trifluoromethyl)phenoxy]phenyl]ethanone (90mg, 289.04 μmol, 52.2% yield, 90.0% purity) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 7.85-7.83 (m, 1H), 7.46-7.40 (m, 2H), 7.39-7.35 (m,1H), 7.30-7.25 (m, 2H), 7.23 (d, J=4.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),2.59 (s, 3H); ES-LCMS m/z 280.9 [M+H]⁺.

Step 5: 2-Chloro-1-(2-(3-(trifluoromethyl)phenoxy)phenyl)ethan-1-one

To a mixture of 1-[2-[3-(trifluoromethyl)phenoxy]phenyl]ethanone (90 mg,289.04 μmol, 1 eq) in DCM (2 mL) was added sulphuryl chloride (58.52 mg,433.55 μmol, 43.35 μL, 1.5 eq). The mixture was stirred under N₂ at 0°C. for 2 h. The reaction mixture was quenched by the addition ofsaturated aqueous NaHCO₃ solution (20 mL) at 0° C. The mixture wasconcentrated, diluted with water (10 mL) and extracted with EtOAc (10mL×3). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated to yield a residue which waspurified preparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4um; mobile phase: [water (0.05% HCl)-ACN]; B %: 64%-84%, 10 min),followed by lyophilization to yield2-chloro-1-(2-(3-(trifluoromethyl)phenoxy)phenyl)ethan-1-one (15.56 mg,51.75 μmol, 17.1% yield, 100.0% purity) as a white solid. ¹H NMR (400MHz, CDCl₃) δ ppm 7.96 (d, J=24.0 Hz, 1H), 7.54-7.50 (m, 3H), 7.35 (s,1H), 7.28-7.24 (m, 2H), 6.89-6.88 (m, 1H), 4.77 (s, 2H); ES-LCMS m/z314.9, 316.9 [M+H]⁺.

I-30

Step 1:N-[4-Methyl-3-[[5-(trifluoromethyl)-3-pyridyl]oxy]phenyl]prop-2-enamide

To a stirred solution of N-(3-hydroxy-4-methyl-phenyl)prop-2-enamide(100 mg, 536.12 μmol, 1 eq) in 1,4-dioxane (3 mL) was added K₃PO₄(227.60 mg, 1.07 mmol, 2 eq), CuI (5.11 mg, 26.81 μmol, 0.05 eq),pyridine-2-carboxylic acid (6.60 mg, 53.61 μmol, 0.1 eq) and3-bromo-5-(trifluoromethyl)pyridine (109.04 mg, 482.51 μmol, 0.9 eq).The reaction mixture was at 120° C. for 12 h under microwave. Thereaction mixture was filtered through a pad of celite and the filtratewas concentrated to yield a residue which was purified by preparativeHPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water(0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 41%-56%, 14 min). The desiredfraction was lyophilized to yieldN-[4-methyl-3-[[5-(trifluoromethyl)-3-pyridyl]oxy]phenyl]prop-2-enamide(15.97 mg, 49.01 μmol, 9.1% yield, 98.9% purity) as white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 10.22 (s, 1H), 8.75 (s, 1H), 8.61 (d, J=2.6 Hz,1H), 7.72 (s, 1H), 7.47-7.38 (m, 2H), 7.32 (d, J=8.2 Hz, 1H), 6.41-6.32(m, 1H), 6.26-6.17 (m, 1H), 5.74 (dd, J=1.9, 10.1 Hz, 1H), 2.15 (s, 3H);ES-LCMS m z 322.9 [M+H]⁺.

I-31

Step 1: N-(3-Hydroxy-4-methyl-phenyl)prop-2-enamide

To a solution of 5-amino-2-methyl-phenol (480 mg, 3.90 mmol, 1 eq) inTHE (10 mL) was added DIEA (1.51 g, 11.69 mmol, 2.04 mL, 3 eq) andprop-2-enoyl chloride (352.77 mg, 3.90 mmol, 317.81 μL, 1 eq). Themixture was stirred at 25° C. for 1 h. The reaction mixture wasconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=200/1 to 1/1,TLC: PE/EtOAc=1/1, R_(f)=0.35) to yieldN-(3-hydroxy-4-methyl-phenyl)prop-2-enamide (560 mg, 3.00 mmol, 77.0%yield, 95.0% purity) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ ppm7.26 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.87 (dd, J=2.2, 8.0 Hz,1H), 6.46-6.35 (m, 1H), 6.35-6.29 (m, 1H), 5.73 (dd, J=2.0, 9.8 Hz, 1H),2.14 (s, 3H); ES-LCMS m/z 178.0 [M+H]⁺.

Step 2:N-[4-methyl-3-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enamide

To a stirred solution of N-(3-hydroxy-4-methyl-phenyl)prop-2-enamide(100 mg, 536.12 μmol, 1 eq) in 1,4-dioxane (3 mL) was added2-bromo-4-(trifluoromethyl)pyridine (109.04 mg, 482.51 μmol, 0.9 eq),K₃PO₄ (227.60 mg, 1.07 mmol, 2 eq), pyridine-2-carboxylic acid (6.60 mg,53.61 μmol, 0.1 eq) and CuI (5.11 mg, 26.81 μmol, 0.05 eq). The reactionmixture was stirred at 120° C. in microwave (3 bar) for 12 h. Thereaction mixture was quenched by addition of water (50 mL), extractedwith EtOAc (50 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by preparative HPLC(column: Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 43%-73%, 10 min), followed by lyophilization toyieldN-[4-methyl-3-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enamide(50 mg, 154.52 μmol, 27.3% yield, 99.6% purity) as a brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.18 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.52 (d,J=2.0 Hz, 1H), 7.49-7.42 (m, 2H), 7.37 (dd, J=2.0, 8.2 Hz, 1H), 7.25 (d,J=8.2 Hz, 1H), 6.44-6.31 (m, 1H), 6.26-6.10 (m, 1H), 5.76-5.66 (m, 1H),2.01 (s, 3H); ES-LCMS m/z 323.0 [M+H]⁺.

I-32

Step 1: 3-[2-Methoxy-5-(trifluoromethyl)phenoxy]-4-methyl-aniline

To a stirred solution of 3-iodo-4-methyl-aniline (200 mg, 858.19 μmol, 1eq) in DMSO (5 mL) was added K₃PO₄ (364.34 mg, 1.72 mmol, 2 eq), CuI(8.17 mg, 42.91 μmol, 0.05 eq), pyridine-2-carboxylic acid (10.57 mg,85.82 μmol, 0.1 eq) and 2-methoxy-5-(trifluoromethyl)phenol (164.89 mg,858.19 μmol, 1 eq). The reaction mixture was at 120° C. for 12 h underN₂ atmosphere. The reaction mixture was diluted with EtOAc (50 mL) thenwashed with saturated NaCl solution (30 mL×2). The aqueous phase wasextracted with EtOAc (50 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.45) to yield3-[2-methoxy-5-(trifluoromethyl)phenoxy]-4-methyl-aniline (110 mg,360.41 μmol, 42.0% yield, 97.4% purity) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.47 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 6.97 (d,J=1.7 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.28 (dd, J=2.0, 8.1 Hz, 1H),5.96 (d, J=2.0 Hz, 1H), 4.99 (s, 2H), 3.87 (s, 3H), 2.04-1.96 (m, 3H);ES-LCMS m/z 298.0 [M+H]⁺.

Step 2:N-[3-[2-Methoxy-5-(trifluoromethyl)phenoxy]-4-methyl-phenyl]prop-2-enamide

To a stirred solution of3-[2-methoxy-5-(trifluoromethyl)phenoxy]-4-methyl-aniline (110 mg,360.41 μmol, 1 eq) in THE (3 mL) was added DIEA (139.74 mg, 1.08 mmol,188.33 μL, 3 eq) and prop-2-enoyl chloride (65.24 mg, 720.82 μmol, 58.78μL, 2 eq). The reaction mixture was at 25° C. for 1 h under N₂atmosphere. The reaction mixture was concentrated to yield a residuewhich was purified by preparative HPLC (column: YMC Triart 30*150 mm*7um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:57%-77%, 10 min). The desired fraction was lyophilized to yieldN-[3-[2-methoxy-5-(trifluoromethyl)phenoxy]-4-methyl-phenyl]prop-2-enamide(65.11 mg, 185.33 μmol, 51.4% yield, 100.0% purity) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.06 (s, 1H), 7.60-7.53 (m, 1H), 7.41-7.31(m, 2H), 7.25-7.17 (m, 2H), 7.04 (d, J=1.7 Hz, 1H), 6.39-6.27 (m, 1H),6.22-6.14 (m, 1H), 5.74-5.66 (m, 1H), 3.85 (s, 3H), 2.19 (s, 3H);ES-LCMS m/z 352.0 [M+H]⁺.

I-4

Step 1: Methyl 3-methyl-2-[3-(trifluoromethyl)anilino]benzoate

To a mixture of methyl 2-amino-3-methyl-benzoate (3.91 g, 23.69 mmol,1.5 eq) and [3-(trifluoromethyl)phenyl]boronic acid (3 g, 15.80 mmol,1.41 mL, 1 eq) in DCM (50 mL) was added Cu(OAc)₂ (3.44 g, 18.95 mmol,1.2 eq) and DIEA (4.08 g, 31.59 mmol, 5.50 mL, 2 eq). The mixture wasstirred under oxygen (15 psi) atmosphere at 25° C. for 12 h. TLC(PE/EtOAc=10/1, R_(f)=0.60) showed starting material was consumed andone major new spot was detected. The mixture was filtered and thefiltrate was concentrated to yield a residue which was purified by flashsilica gel chromatography (from pure PE to PE/EtOAc=10/1, TLC:PE/EtOAc=10/1, R_(f)=0.60) to yield methyl3-methyl-2-[3-(trifluoromethyl)anilino]benzoate (1.4 g, 4.07 mmol, 25.8%yield, 90.0% purity) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27(s, 1H), 7.66 (dd, J=1.2, 7.8 Hz, 1H), 7.53 (d, J=6.8 Hz, 1H), 7.33 (t,J=7.9 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.83 (s,1H), 6.76 (dd, J=2.0, 8.1 Hz, 1H), 3.64 (s, 3H), 2.13 (s, 3H); ES-LCMSm/z 310.0 [M+H]⁺.

Step 2: 3-Methyl-2-[3-(trifluoromethyl)anilino]benzoic Acid

To a mixture of methyl 3-methyl-2-[3-(trifluoromethyl)anilino]benzoate(1.4 g, 4.07 mmol, 1 eq) in THE (5 mL), H₂O (5 mL) and ACN (5 mL) wasadded LiOH (487.82 mg, 20.37 mmol, 5 eq) and stirred at 25° C. for 12 h.TLC (PE/EtOAc=1/1, R_(f)=0.4) showed starting material was consumed, andone major new spot was detected. The reaction mixture was concentrated,diluted with H₂O (20 mL), acidified with 1 N HCl (20 mL, adjust pH to 5)and extracted with EtOAc (20 mL×3). The combine organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated to yield3-methyl-2-[3-(trifluoromethyl)anilino]benzoic acid (1.3 g, 3.96 mmol,97.3% yield, 90.0% purity) as colorless oil. ¹H NMR (500 MHz, DMSO-d₆) δppm 12.96 (br s, 1H), 8.46 (br s, 1H), 7.77-7.68 (m, 1H), 7.50 (d, J=6.7Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.02 (d, J=7.6Hz, 1H), 6.85 (s, 1H), 6.77 (d, J=8.1 Hz, 1H), 2.09 (s, 3H).

Step 3: N-Methoxy-N,3-dimethyl-2-[3-(trifluoromethyl)anilino]benzamide

To a mixture of 3-methyl-2-[3-(trifluoromethyl)anilino]benzoic acid (1.3g, 3.96 mmol, 1 eq) and N-methoxymethanamine (773.07 mg, 7.93 mmol, 2eq, HCl) in DCM (20 mL) was added HATU (1.81 g, 4.76 mmol, 1.2 eq) andDIEA (1.54 g, 11.89 mmol, 2.07 mL, 3 eq). The mixture was stirred at 60°C. for 12 h. TLC (PE/EtOAc=5/1, R_(f)=0.5) showed starting material wasconsumed and one major new spot was detected. The mixture was dilutedwith H₂O (40 mL) and extracted with EtOAc (50 mL×3). The combine organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated toyield a residue which was purified by flash silica gel chromatography(from pure PE to PE/EtOAc=3/1, TLC: PE/EtOAc=5/1, R_(f)=0.5) to yieldN-methoxy-N,3-dimethyl-2-[3-(trifluoromethyl)anilino]benzamide (1.4 g,3.31 mmol, 83.5% yield, 80.0% purity) as colorless oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.82 (br s, 1H), 7.38 (t, J=4.5 Hz, 1H), 7.29-7.21 (m,3H), 6.90 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.73-6.67 (m, 1H), 3.37 (s,3H), 3.04 (br s, 3H), 2.11 (s, 3H).

Step 4: 1-[3-Methyl-2-[3-(trifluoromethyl)anilino]phenyl]ethanone

To a solution ofN-methoxy-N,3-dimethyl-2-[3-(trifluoromethyl)anilino]benzamide (1.4 g,3.31 mmol, 1 eq) in THE (40 mL) was added MeMgBr (3 M, 11.03 mL, 10 eq)under N2 atmosphere at −78° C. and stirred under N₂ atmosphere at 25° C.for 12 h. TLC (PE/EtOAc=3:1, R_(f)=0.60) showed starting material wasremained and one major new spot was detected. Then to the mixture wasadded MeMgBr (3 M, 7.72 mL, 7 eq) at 0° C. and stirred at 25° C. for 12h. TLC (PE/EtOAc=3/1, R_(f)=0.60) showed starting material was consumedand one major new spot was detected. The mixture was added saturatedNH₄Cl (300 mL) and extracted with EtOAc (150 mL×3). The combine organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated toyield a residue which was purified by flash silica gel chromatography(from pure PE to PE/EtOAc=5/1, TLC: PE/EtOAc=5/1, R_(f)=0.60) to yield1-[3-methyl-2-[3-(trifluoromethyl)anilino]phenyl]ethanone (450 mg, 1.38mmol, 41.7% yield, 90.0% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.52 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.2 Hz,1H), 7.34 (t, J=7.9 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.00 (d, J=7.6 Hz,1H), 6.80 (s, 1H), 6.75 (d, J=8.2 Hz, 1H), 2.41 (s, 3H), 2.13-2.08 (m,1H), 2.11 (s, 3H); ES-LCMS m/z 294.0 [M+H]⁺.

Step 5:2-Chloro-1-[3-methyl-2-[3-(trifluoromethyl)anilino]phenyl]ethanone

To a solution of1-[3-methyl-2-[3-(trifluoromethyl)anilino]phenyl]ethanone (160 mg,490.99 μmol, 1 eq) in DCM (3 mL) was added DIEA (380.74 mg, 2.95 mmol,513.13 μL, 6 eq) and TMSOTf (654.76 mg, 2.95 mmol, 532.33 μL, 6 eq) at0° C. and stirred at 25° C. for 2 h. Then to the mixture was added NCS(131.13 mg, 981.99 μmol, 2 eq) and stirred at 25° C. for 10 h. TLC(PE/EtOAc=3/1, R_(f)=0.60) showed starting material was consumed and onemajor new spot was detected. The mixture was diluted with H₂O (20 mL)and extracted with EtOAc (20 mL×3). The combine organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated to yield aresidue which was purified by preparative TLC (PE/EtOAc=3/1, TLC:PE/EtOAc=3/1, R_(f)=0.60) and then by preparative HPLC (column: WelchXtimate C18 150*25 mm*5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 56%-86%, 10 min) and lyophilized to yield2-chloro-1-[3-methyl-2-[3-(trifluoromethyl)anilino]phenyl]ethanone(16.87 mg, 51.48 μmol, 10.5% yield, 100.0% purity) as a yellow solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 9.09 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.45(d, J=7.5 Hz, 1H), 7.35-7.29 (m, 1H), 7.18-7.11 (m, 2H), 6.91-6.87 (m,2H), 4.74 (s, 2H), 2.07 (s, 3H); ES-LCMS m/z 328.1, 330.1, 332.1 [M+H]⁺.

I-3

Step 1:3-(2-Chloroacetyl)-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide

To a solution of3-acetyl-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide (200mg, 530.67 μmol, 1 eq) in DCM (3 mL) was added DIEA (205.76 mg, 1.59mmol, 277.30 μL, 3 eq) and TMSOTf (353.84 mg, 1.59 mmol, 287.67 μL, 3eq) at 0° C. The mixture was stirred at 25° C. for 2 h. NIS (179.09 mg,796.00 μmol, 1.5 eq) was added at 25° C. The mixture was stirred at 25°C. for 2 h. The reaction mixture was concentrated under reduced pressureto yield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 8/1, TLC: PE/EtOAc=2/1, R_(f)=0.55). The desiredfraction was concentrated under reduced pressure to yield a residuewhich was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 43%-73%, 10min). The desired fraction was lyophilized to yield3-(2-chloroacetyl)-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(18.97 mg, 46.63 μmol, 8.8% yield, 100.0% purity) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 10.83 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.78(dd, J=2.0, 9.0 Hz, 1H), 7.60-7.51 (m, 3H), 7.47 (d, J=7.8 Hz, 1H), 7.23(d, J=9.4 Hz, 1H), 4.78 (s, 2H), 4.40-4.33 (m, 1H), 2.71 (d, J=5.1 Hz,3H); ES-LCMS m/z 406.9 [M+H]⁺.

I-33

Step 1: N-(4-Methyl-3-nitro-phenyl)prop-2-enamide

To a solution of 4-methyl-3-nitro-aniline (2 g, 13.14 mmol, 1 eq) andDIEA (5.10 g, 39.43 mmol, 6.87 mL, 3 eq) in DCM (20 mL) was addedprop-2-enoyl chloride (1.31 g, 14.46 mmol, 1.18 mL, 1.1 eq) dropwise at25° C. The mixture was stirred at 25° C. for 1 h. TLC (PE/EtOAc=2/1,R_(f)=0.30) showed the starting material was consumed completely. Thereaction mixture was quenched with H₂O (50 mL) and extracted with DCM(50 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yieldN-(4-methyl-3-nitro-phenyl)prop-2-enamide (2.68 g, 12.70 mmol, 96.6%yield, 97.7% purity) as a yellow solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (d,J=2.0 Hz, 1H), 7.89-7.81 (m, 1H), 7.72 (s, 1H), 7.31 (d, J=8.2 Hz, 1H),6.52-6.46 (m, 1H), 6.33-6.23 (m, 1H), 5.83 (dd, J=1.0, 10.4 Hz, 1H),2.57 (s, 3H); ES-LCMS m/z 207.0 [M+H]⁺.

Step 2: N-(3-Amino-4-methyl-phenyl)prop-2-enamide

A mixture of N-(4-methyl-3-nitro-phenyl)prop-2-enamide (2.68 g, 12.70mmol, 1 eq), Fe (7.09 g, 126.98 mmol, 10 eq) and NH₄Cl (6.79 g, 126.98mmol, 10 eq) in THE (20 mL), EtOH (20 mL) and H₂O (20 mL) was stirred at55° C. for 4 h. TLC (PE/EtOAc=1/1, R_(f)=0.20) showed the startingmaterial was consumed completely. The mixture was filtered. The filtratewas diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield N-(3-amino-4-methyl-phenyl)prop-2-enamide (2.2g, 11.86 mmol, 93.4% yield, 95.0% purity) as a brown solid, which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.23 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.67 (d, J=7.4 Hz,1H), 6.48-6.36 (m, 1H), 6.31-6.14 (m, 1H), 5.74 (d, J=10.2 Hz, 1H), 3.66(s, 2H), 2.13 (s, 3H).

Step 3: N-[4-Methyl-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide

A mixture of N-(3-amino-4-methyl-phenyl)prop-2-enamide (1 g, 5.39 mmol,1 eq), [3-(trifluoromethyl)phenyl]boronic acid (2.05 g, 10.78 mmol, 2eq), Cu(OAc)₂ (2.15 g, 11.86 mmol, 2.2 eq) and DIEA (2.09 g, 16.17 mmol,2.82 mL, 3 eq) in DCM (20 mL) was stirred under 02 (15 psi) at 25° C.for 12 h. TLC (PE/EtOAc=1/1, R_(f)=0.52) showed the starting materialwas consumed completely. The reaction mixture was diluted with H₂O (50mL) and filtered. The filtrate was extracted with DCM (50 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=1/1,R_(f)=0.52) to yieldN-[4-methyl-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide (850 mg,2.65 mmol, 49.2% yield, 100.0% purity) as a yellow solid. ¹H NMR (500MHz, CDCl₃) δ ppm 7.52 (s, 1H), 7.37-7.31 (m, 1H), 7.27 (s, 1H), 7.19(s, 2H), 7.14-7.08 (m, 3H), 6.41 (d, J=16.6 Hz, 1H), 6.22 (dd, J=10.4,16.8 Hz, 1H), 5.80-5.68 (m, 1H), 5.55 (s, 1H), 2.22 (s, 3H); ES-LCMS m/z321.0 [M+H]⁺.

I-34

Step 1: 7-Nitro-1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinoline

To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (400 mg, 2.24 mmol,1 eq) and 1-iodo-4-(trifluoromethyl)benzene (1.22 g, 4.49 mmol, 660.11μL, 2 eq) in toluene (10 mL) was added Pd(OAc)₂ (50.40 mg, 224.48 μmol,0.1 eq), XPhos (214.03 mg, 448.97 μmol, 0.2 eq) and Cs₂CO₃ (2.19 g, 6.73mmol, 3 eq) under N₂ atmosphere. The mixture was stirred at 100° C. for12 h. To the mixture was added water (50 mL) and extracted with ethylacetate (50 mL×3). The combined organic phase was washed with brine (20mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=200/1 to 5/1, TLC: PE/EtOAc=5/1, R_(f)=0.40) to yield7-nitro-1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinoline (580 mg,1.80 mmol, 80.1% yield, 100% purity) as a yellow solid. ¹H NMR (500 MHz,CD₃OD) δ ppm 7.69 (d, J=8.5 Hz, 2H), 7.62 (d, J=2.1 Hz, 1H), 7.58 (dd,J=2.3, 8.2 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H),3.76-3.71 (m, 2H), 2.94 (t, J=6.4 Hz, 2H), 2.09 (q, J=6.1 Hz, 2H);ES-LCMS m/z 323.0 [M+H]⁺.

Step 2: 1-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-amine

To a solution of7-nitro-1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinoline (200 mg,620.58 μmol, 1 eq) in MeOH (15 mL) was added Pd/C (200 mg, 10%) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 25° C. for 2 h. Thereaction mixture was filtered and concentrated to yield the residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=200/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.47) to yield1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-amine (120 mg,348.96 μmol, 56.2% yield, 85.0% purity) as yellow oil. ¹H NMR (500 MHz,CD₃OD) δ ppm 7.52 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 6.85 (d,J=7.9 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 6.29 (dd, J=2.1, 7.9 Hz, 1H),3.62 (t, J=6.0 Hz, 2H), 2.67 (t, J=6.4 Hz, 2H), 1.95 (q, J=6.2 Hz, 2H);ES-LCMS m/z 293.0 [M+H]⁺.

Step 3:N-[1-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-yl]prop-2-enamide

To a solution of1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-amine (90 mg,261.72 μmol, 1 eq) in THE (5 mL) was added prop-2-enoyl chloride (47.38mg, 523.44 μmol, 42.68 μL, 2 eq) and DIEA (101.47 mg, 785.16 μmol,136.76 μL, 3 eq). The mixture was stirred at 25° C. for 1 h. To themixture was added water (30 mL) and extracted with ethyl acetate (30mL×3). The combined organic phase was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=200/1 to 5/1, TLC: PE/EtOAc=5/1, R_(f)=0.40) to yield aproduct. The product was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.04% NH3-1H₂O+10 mMNH₄HCO₃)-ACN]; B %: 52%-82%, 10 min), followed by lyophilization toyieldN-[1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-yl]prop-2-enamide(47.63 mg, 137.52 μmol, 52.6% yield, 100% purity) as a white solid.¹HNMR (500 MHz, CD₃OD) δ ppm 7.57 (d, J=8.7 Hz, 2H), 7.40-7.33 (m, 3H),7.09-7.02 (m, 2H), 6.41-6.22 (m, 2H), 5.69 (dd, J=1.8, 9.9 Hz, 1H),3.72-3.64 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.02 (q, J=6.1 Hz, 2H);ES-LCMS m/z 347.0 [M+H]⁺.

I-46

Step 1: Tert-ButylN-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]carbamate

To a solution of tert-butyl N-(4-piperidyl)carbamate (450 mg, 2.25 mmol,1 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (483.37 mg, 2.02mmol, 311.85 μL, 0.9 eq) in DCM (10 mL) was added DIEA (435.59 mg, 3.37mmol, 587.05 μL, 1.5 eq). The mixture was stirred at 25° C. for 1 h. Tothe mixture was added water (30 mL) and extracted with DCM (30 mL×3).The combined organic phase was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=200/1 to 5/1, TLC: PE/EtOAc=3/1, R_(f)=0.32) to yieldtert-butylN-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]carbamate (590 mg,1.65 mmol, 73.3% yield, 100% purity) as a white solid. ¹H NMR (500 MHz,CD₃OD) δ ppm 7.62 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 3.59 (s,2H), 2.83 (d, J=11.9 Hz, 2H), 2.13 (t, J=11.3 Hz, 2H), 1.84 (d, J=11.6Hz, 2H), 1.51-1.45 (m, 2H), 1.44-1.41 (m, 9H).

Step 2: 1-[[4-(Trifluoromethyl)phenyl]methyl]piperidin-4-amine

A mixture of tert-butylN-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]carbamate (550 mg,1.53 mmol, 1 eq) in HCl/MeOH (10 mL, 4 M) was stirred at 25° C. for 1 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure to yield a residue which was neutralized by addition of sat.aq. NaHCO₃ (5 mL), and to the mixture was added water (30 mL) andextracted with ethyl acetate (30 mL×3). The combined organic phase waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum to yield1-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-amine (350 mg, 1.36mmol, 88.3% yield, 100% purity) as a yellow solid which was used in thenext step without further purification. ¹H NMR (500 MHz, CD₃OD) δ ppm7.82 (s, 4H), 4.45 (s, 2H), 3.59 (d, J=11.9 Hz, 2H), 3.49 (s, 1H), 3.22(s, 2H), 2.26 (d, J=13.4 Hz, 2H), 2.12-1.97 (m, 2H); ES-LCMS m/z 259.0[M+1]⁺.

Step 3:N-[1-[[4-(Trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide

To a solution of 1-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-amine(300 mg, 1.16 mmol, 1 eq) in THF (5 mL) was added prop-2-enoyl chloride(210.25 mg, 2.32 mmol, 189.42 μL, 2 eq) and DIEA (450.34 mg, 3.48 mmol,606.93 μL, 3 eq). The mixture was stirred at 25° C. for 1 h. To themixture was added water (30 mL) and extracted with ethyl acetate (30mL×3). The combined organic phase was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to yield aresidue which was purified by preparative HPLC (column: Agela DuraShellC18 150*25 mm*5 μm; mobile phase: [water (0.04% NH₃—H₂O+10 mMNH₄HCO₃)-ACN]; B %: 30%-60%, 10 min), followed by lyophilization toyieldN-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide(72.71 mg, 232.80 μmol, 20.0% yield, 100% purity) as a white solid. ¹HNMR (500 MHz, CD₃OD) δ ppm 7.63 (d, J=8.1 Hz, 2H), 7.54 (d, J=7.9 Hz,2H), 6.28-6.17 (m, 2H), 5.63 (dd, J=3.8, 8.2 Hz, 1H), 3.81-3.69 (m, 1H),3.61 (s, 2H), 2.88 (d, J=12.1 Hz, 2H), 2.17 (t, J=11.1 Hz, 2H), 1.88 (d,J=12.4 Hz, 2H), 1.56 (dq, J=3.6, 11.9 Hz, 2H); ES-LCMS m/z 313.0 [M+H]⁺.

I-47

Step 1: Tert-butyl (3R)-3-(prop-2-enoylamino)piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (500mg, 2.50 mmol, 1 eq) in DCM (15 mL) was added Et₃N (757.87 mg, 7.49mmol, 1.04 mL, 3 eq) and prop-2-enoyl chloride (271.15 mg, 3.00 mmol,244.28 μL, 1.2 eq). The mixture was stirred at 25° C. for 2 h. Thereaction mixture was quenched by addition of NH₄Cl (aq, 20 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to tert-Butyl(3R)-3-(Prop-2-Enoylamino)piperidine-1-Carboxylate (650 mg, 2.43 mmol,97.3% yield, 95.0% purity) as a colorless oil, which was used in thenext step without further purification. ¹H NMR (500 MHz, CDCl₃) δ ppm6.27 (d, J=17.0 Hz, 1H), 6.06 (dd, J=10.0 Hz, 17.0 Hz, 1H), 5.64 (d,J=10.5 Hz, 1H), 4.06-4.01 (m, 1H), 3.50-3.20 (m, 4H), 1.85-1.50 (m, 5H),1.45 (s, 9H). ES-LCMS m z no found.

Step 2: N-[(3R)-3-piperidyl]prop-2-enamide

To a solution of tert-butyl(3R)-3-(Prop-2-Enoylamino)piperidine-1-carboxylate (650 mg, 2.43 mmol, 1eq) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at 28°C. for 2 h. TLC (PE/EtOAc=2/1, R_(f)=0.1) showed that new point wasformed and start material was consumed completely. The mixture wasconcentrated to give N-[(3R)-3-Piperidyl]prop-2-Enamide (350 mg, 1.82mmol, 74.8% yield, 80.0% purity) as a white solid, which was used in thenext step without further purification. ES-LCMS m z no found.

Step 3:N-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]prop-2-enamide

To a solution of N-[(3R)-3-Piperidyl]prop-2-Enamide (350 mg, 1.82 mmol,1 eq) in DCM (8 mL) was added Et₃N (183.73 mg, 1.82 mmol, 252.73 μL, 1eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (434.01 mg, 1.82mmol, 276.44 μL, 1 eq). The mixture was stirred at 28° C. for 1 h. Thereaction mixture was quenched by addition of aqueous solution of NH₄Cl(20 mL) and extracted with EtOAc (20 mL×3). The combined organic layerswere washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue which was purifiedby preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 36%-66%, 10 min) to yieldN-[(3R)-1-[[3-(Trifluoromethyl)phenyl]methyl]-3-Piperidyl]prop-2-Enamide(19.93 mg, 62.28 μmol, 3.4% yield, 97.6% purity, R_(t)=1.862, ee=99.82%,[α]^(30.5) _(D)=+26 (MeOH, c=0.100 g/100 mL)) as a white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 7.96 (d, J=7.5 Hz, 1H), 7.66-7.59 (m, 3H),7.58-7.53 (m, 1H), 6.22 (dd, J=10.0, 17.0 Hz, 1H), 6.04 (dd, J=2.0, 17.0Hz, 1H), 5.55 (dd, J=2.0, 10.0 Hz, 1H), 3.85-3.75 (m, 1H), 3.57 (s, 2H),2.72 (d, J=8.5 Hz, 1H), 2.64-2.57 (m, 1H), 2.01 (t, J=10.0 Hz, 1H), 1.87(t, J=10.0 Hz, 1H), 1.78-1.60 (m, 2H), 1.54-1.43 (m, 1H), 1.25-1.13 (m,1H); ES-LCMS m/z 313.2 [M+H]⁺.

I-48

Step 1: Tert-butyl (3S)-3-(prop-2-enoylamino)piperidine-1-carboxylate

To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate (200mg, 998.61 μmol, 316.46 μL, 1 eq) in THE (5 mL) was added TEA (202.10mg, 2.00 mmol, 277.99 μL, 2 eq) and prop-2-enoyl chloride (99.42 mg,1.10 mmol, 89.57 μL, 1.1 eq) under N₂. The mixture was stirred at 25° C.for 1 h. TLC (PE/EtOAc=5/1, R_(f)=0.60) indicated the starting materialwas consumed completely and one new spot formed. The mixture wasconcentrated and NaHCO₃ (40 mL) was added. The mixture was extractedwith EtOAc (40 mL×3), washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to yield tert-butyl(3S)-3-(prop-2-enoylamino)piperidine-1-carboxylate (100 mg, 382.78 μmol,38.3% yield, 97.4% purity) as a white solid which was used in the nextstep directly without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 6.28 (d, J=16.8 Hz, 1H), 6.13-5.98 (m, 1H), 5.66 (d, J=11.3 Hz, 1H),4.06 (s, 1H), 3.49-3.47 (m, 3H), 3.33-3.30 (m, 1H), 1.83-1.81 (m, 4H),1.46 (s, 9H); ES-LCMS m z 255.1 [M+H]⁺.

Step 2: N-[(3S)-3-piperidyl]prop-2-enamide

To a solution of tert-butyl(3S)-3-(prop-2-enoylamino)piperidine-1-carboxylate (100 mg, 382.78 μmol,1 eq) in DCM (5 mL) was added TFA (1.34 g, 11.74 mmol, 869.57 μL, 30.68eq) under N₂. The mixture was stirred at 25° C. for 12 h. The reactionmixture was concentrated under reduced pressure to yieldN-[(3S)-3-piperidyl]prop-2-enamide (102 mg, 361.25 μmol, 94.4% yield,95.0% purity, TFA salt) as a light white solid which was used in nextstep directly without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 6.34-6.28 (m, 1H), 6.21-6.13 (m, 1H), 5.76 (d, J=10.2 Hz, 1H), 4.43(s, 1H), 3.33-3.30 (m, 1H), 3.36-3.27 (m, 1H), 3.16-3.13 (m, 1H),1.92-1.89 (m, 4H).

Step 3:N-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]prop-2-enamide

To a solution of N-[(3S)-3-piperidyl]prop-2-enamide (100 mg, 354.17μmol, 1 eq, TFA) in DCM (5 mL) were added1-(bromomethyl)-3-(trifluoromethyl)benzene (84.66 mg, 354.17 μmol, 53.92μL, 1 eq) and TEA (179.19 mg, 1.77 mmol, 246.48 μL, 5 eq). The mixturewas stirred at 25° C. for 1 h under N₂. The reaction mixture wasconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5μm; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %:37%-67%, 10 min), followed by lyophilization to yieldN-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]prop-2-enamide(51.03 mg, 160.12 μmol, 45.2% yield, 98.0% purity, SFC: R_(t)=2.032,ee=99.28%, [α]^(30.6) _(D)=−33 (MeOH, c=0.1 g/100 mL)) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (d, J=8.2 Hz, 1H), 7.64-7.53 (m,4H), 6.26-6.15 (m, 1H), 6.07-5.99 (m, 1H), 5.54 (dd, J=2.3, 10.2 Hz,1H), 3.88-3.73 (m, 1H), 3.56 (s, 2H), 2.70 (d, J=10.2 Hz, 1H), 2.59 (d,J=11.0 Hz, 1H), 2.01 (t, J=10.4 Hz, 1H), 1.86 (t, J 9.8 Hz, 1H),1.74-1.64 (m, 2H), 1.54-1.43 (m, 1H), 1.24-1.13 (m, 1H); ES-LCMS m/z313.0 [M+H]⁺.

P-10

Step 1: Methyl 4-amino-3-(2-methyltetrazol-5-yl)benzoate

To a stirred solution of methyl4-(benzylamino)-3-(2-methyltetrazol-5-yl)benzoate (400 mg, 1.24 mmol, 1eq) in MeOH (50 mL) was added Pd/C (0.4 g, 10% Pd in C in 50% water)slowly. The reaction mixture was stirred at 25° C. for 12 h under H₂atmosphere (45 psi). TLC (PE/EtOAc=1/1, R_(f)=0.30) showed startingmaterial was remained and one new spot was detected. The reactionmixture was filtered through a pad of celite. The filtrate wasconcentrated under reduced pressure to give a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=100/1 to 1/1, TLC:PE/EtOAc=1/1, R_(f)=0.30) to yield methyl4-amino-3-(2-methyltetrazol-5-yl)benzoate (200 mg, 857.54 μmol, 69.3%yield, 100.0% purity) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.58 (d, J=2.0 Hz, 1H), 7.76 (dd, J=2.0, 8.6 Hz, 1H), 7.07 (s, 2H), 6.92(d, J=8.8 Hz, 1H), 4.46 (s, 3H), 3.80 (s, 3H).

Step 2:N-methyl-3-(4-methyl-1H-imidazol-2-yl)-4-[3-(trifluoromethyl)phenoxy]benzenesulfonamide

To a stirred solution of methyl4-amino-3-(2-methyltetrazol-5-yl)benzoate (180 mg, 771.78 umol, 1 eq)and [3-(trifluoromethyl)phenyl]boronic acid (366.46 mg, 1.93 mmol, 2.5eq) in DCM (10 mL) was added Cu(OAc)₂ (280.36 mg, 1.54 mmol, 2 eq) andDIEA (299.24 mg, 2.32 mmol, 403.29 μL, 3 eq). The reaction mixture wasstirred at 25° C. for 48 h under oxygen atmosphere (15 psi). Thereaction mixture was diluted with water (50 mL) then extracted with DCM(30 mL×3). The combined organic layers were dried over Na₂SO₄, filteredand the filtrate was concentrated to yield a residue which was purifiedby preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobilephase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 55%-85%, 10 min).The desired fraction was lyophilized to yield methyl3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzoate (215.65mg, 571.53 μmol, 74.1% yield, 100.0% purity) as white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.20 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 7.94 (dd,J=2.0, 8.8 Hz, 1H), 7.66-7.58 (m, 3H), 7.45 (d, J=6.8 Hz, 1H), 7.39 (d,J=8.8 Hz, 1H), 4.49 (s, 3H), 3.85 (s, 3H); ES-LCMS m/z 378.0 [M+H]⁺.

I-35

Step 1:N-[4-methyl-3-[N-methyl-3-(trifluoromethyl)anilino]phenyl]prop-2-enamide

To a solution ofN-[4-methyl-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide (300 mg,936.60 μmol, 1 eq) in DCM (10 mL) and AcOH (0.5 mL) was addedparaformaldehyde (100 mg). The mixture was stirred at 25° C. for 1 h.NaBH₃CN (200 mg, 3.18 mmol, 3.40 eq) was added. The mixture was stirredat 25° C. for 11 h. TLC (PE/EtOAc=3/1, R_(f)=0.36) showed about 50% ofthe starting material was consumed completely. The reaction mixture wasdiluted with H₂O (50 mL) and extracted with DCM (50 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by preparative HPLC(column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 47%-77%, 10 min). The desired fraction waslyophilized to yield a residue which was purified by preparative HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.05% HCl)-ACN]; B %: 60%-80%, 10 min). The desired fraction wasbasified with saturated aqueous NaHCO₃ until pH=8 and extracted withEtOAc (50 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and water (10 mL) and lyophilized to yieldN-[4-methyl-3-[N-methyl-3-(trifluoromethyl)anilino]phenyl]prop-2-enamide(45.32 mg, 135.55 μmol, 14.5% yield, 100.0% purity) as a white solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.52-7.38 (m, 2H), 7.28 (s, 1H), 7.27 (s,1H), 7.23 (t, J=8.0 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.62(dd, J=1.8, 8.4 Hz, 1H), 6.42 (d, J=16.9 Hz, 1H), 6.22 (dd, J=10.2, 16.8Hz, 1H), 5.77 (d, J=10.2 Hz, 1H), 3.25 (s, 3H), 2.09 (s, 3H); ES-LCMSm/z 335.0 [M+H]⁺.

I-36

Step 1: N-(4-bromo-3-nitro-phenyl)prop-2-enamide

To a mixture of 4-bromo-3-nitro-aniline (3 g, 13.82 mmol, 1 eq) and DIEA(5.36 g, 41.47 mmol, 7.22 mL, 3 eq) in DCM (20 mL) was addedprop-2-enoyl chloride (1.50 g, 16.59 mmol, 1.35 mL, 1.2 eq) dropwise at0° C. The mixture was stirred at 25° C. for 2 h. TLC (PE/EtOAc=1/1,R_(f)=0.35) showed the starting material was consumed completely. Thereaction mixture was diluted with H₂O (50 mL) and extracted with DCM (50mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yieldN-(4-bromo-3-nitro-phenyl)prop-2-enamide (3.7 g, 10.92 mmol, 79.0%yield, 80.0% purity) as a white solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.26 (d,J=2.3 Hz, 1H), 8.15 (s, 1H), 7.79 (dd, J=2.5, 8.8 Hz, 1H), 7.66 (d,J=9.0 Hz, 1H), 6.54-6.51 (m, 1H), 6.38-6.28 (m, 1H), 5.84 (dd, J=1.0,10.0 Hz, 1H); ES-LCMS m/z 270.9, 272.9 [M+H]⁺.

Step 2: N-(3-amino-4-bromo-phenyl)prop-2-enamide

A mixture of N-(4-bromo-3-nitro-phenyl)prop-2-enamide (3.7 g, 10.92mmol, 1 eq), Fe (3.05 g, 54.60 mmol, 5 eq) and NH₄Cl (2.92 g, 54.60mmol, 5 eq) in THE (15 mL), EtOH (15 mL) and H₂O (15 mL) was stirred at55° C. for 12 h. TLC (PE/EtOAc=1/1, R_(f)=0.28) showed the startingmaterial was consumed completely. The mixture was filtered. The filtratewas diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=1/1,R_(f)=0.28) to yield N-(3-amino-4-bromo-phenyl)prop-2-enamide (2.2 g,9.13 mmol, 83.6% yield, 100.0% purity) as a white solid. ¹H NMR (400MHz, CDCl₃) δ ppm 7.43 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.18-7.10 (m,1H), 6.60-6.55 (m, 1H), 6.45-6.40 (m, 1H), 6.25-6.18 (m, 1H), 5.80-5.77(m, 1H), 4.15 (s, 2H); ES-LCMS m/z 240.9, 242.9 [M+H]⁺.

Step 3: N-[4-bromo-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide

To a solution of N-(3-amino-4-bromo-phenyl)prop-2-enamide (2 g, 8.30mmol, 1 eq), [3-(trifluoromethyl)phenyl]boronic acid (3.5 g, 18.43 mmol,2.22 eq), Cu(OAc)₂ (3.77 g, 20.74 mmol, 2.5 eq) and DIEA (3.22 g, 24.89mmol, 4.33 mL, 3 eq) in DCM (40 mL) was stirred under 02 (15 psi) at 25°C. for 12 h. TLC (PE/EtOAc=1/1, R_(f)=0.40) showed about 60% of thestarting material was consumed. The reaction mixture was diluted withH₂O (50 mL) and filtered. The filtrate was extracted with DCM (50 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1,R_(f)=0.40) to yieldN-[4-bromo-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide (1.7 g,3.97 mmol, 47.9% yield, 90% purity) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.61 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.46-7.42 (m, 1H),7.40-7.35 (m, 2H), 7.31-7.24 (m, 2H), 7.10-6.98 (m, 1H), 6.45-6.37 (m,1H), 6.25-6.16 (m, 2H), 5.77 (dd, J=0.9, 10.4 Hz, 1H); ES-LCMS m/z384.9, 386.9 [M+H]⁺.N-[4-Bromo-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide (100 mg,90% purity) was purified by preparative HPLC (column: Phenomenex SynergiC18 150*30 mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 60%-80%,10.5 min). The desired fraction was basified with saturated aqueousNaHCO₃ until pH=8 and extracted with EtOAc (50 mL×3). The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressureto yield a residue which was dissolved in MeCN (10 mL) and water (10 mL)and lyophilized to yieldN-[4-bromo-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide (29.76mg, 99.1% purity) as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ ppm10.23 (s, 1H), 8.05 (s, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.59 (d, J=8.7 Hz,1H), 7.49-7.42 (m, 1H), 7.32-7.24 (m, 3H), 7.16 (d, J=7.6 Hz, 1H),6.44-6.35 (m, 1H), 6.29-6.20 (m, 1H), 5.81-5.72 (m, 1H); ES-LCMS m/z385.0, 387.0 [M+H]⁺.

I-82 & I-83

Step 1: 4-Bromo-1-methyl-2-[3-(trifluoromethyl)phenoxy]benzene

To a mixture of 5-bromo-2-methyl-phenol (1 g, 5.35 mmol, 1 eq) and1-iodo-3-(trifluoromethyl)benzene (1.45 g, 5.35 mmol, 769.48 μL, 1 eq)in DMSO (10 mL) was added CuI (50.91 mg, 267.33 μmol, 0.05 eq),pyridine-2-carboxylic acid (65.82 mg, 534.66 μmol, 0.1 eq) and K₃PO₄(1.82 g, 8.55 mmol, 1.6 eq). The mixture was stirred at 120° C. for 12h. TLC (pure PE, R_(f)=0.80) showed starting material was consumed, andone major new spot was detected. The mixture was filtered and thefiltrate was added H₂O (40 mL) and extracted with EtOAc (80 mL×3). Thecombine organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (pure PE, TLC: pure PE, R_(f)=0.80) to yield4-bromo-1-methyl-2-[3-(trifluoromethyl)phenoxy]benzene (800 mg, crude)as colorless oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.64-7.58 (m, 1H),7.50-7.45 (m, 1H), 7.45-7.29 (m, 2H), 7.28-7.24 (m, 1H), 7.21-7.14 (m,2H), 2.15-2.09 (m, 3H).

Step 2: 1-Methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene

To a solution of 4-bromo-1-methyl-2-[3-(trifluoromethyl)phenoxy]benzene(700 mg, 2.11 mmol, 1 eq) in 1,4-dioxane (9 mL) was added Pd(dppf)Cl₂(154.68 mg, 211.40 μmol, 0.1 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (390.70 mg, 2.54 mmol,430.29 μL, 1.2 eq) and Cs₂CO₃ (2 M, 3.17 mL, 3 eq) under N₂ atmosphere.The mixture was stirred at 80° C. for 0.5 h under N₂ atmosphere. TLC(pure PE, R_(f)=0.75) showed starting material was consumed, and onemajor new spot was detected. To the mixture was added H₂O (20 mL) andextracted with EtOAc (20 mL×3). The combine organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated to yield a residuewhich was purified by flash silica gel chromatography (pure PE, TLC:pure PE, R_(f)=0.75) to yield1-methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene (240 mg, 776.23μmol, 36.7% yield, 90.0% purity) as colorless oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.59-7.56 (m, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.36-7.31 (m,2H), 7.19 (d, J=1.5 Hz, 1H), 7.16-7.11 (m, 2H), 6.69 (dd, J=11.0, 17.7Hz, 1H), 5.80 (d, J=17.7 Hz, 1H), 5.23 (d, J=11.1 Hz, 1H), 2.13 (s, 3H).

Step 3:(5S)-3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazoleand(5R)-3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

To a mixture of 1-methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene(100 mg, 323.43 μmol, 1 eq) and dibromomethanone oxime (78.72 mg, 388.11μmol, 1.2 eq) in EtOAc (6 mL) was added NaHCO₃ (271.71 mg, 3.23 mmol, 10eq). The mixture was stirred at 25° C. for 12 h under N₂ atmosphere. TLC(PE/EtOAc=4/1, R_(f)=0.50) showed starting material was consumedcompletely, and one major new spot was detected. The mixture was dilutedwith H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combine organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated toyield a residue which was purified by preparative TLC (PE/EtOAc=4/1,TLC: PE/EtOAc=4/1, R_(f)=0.50) to yield a residue which was purified bypreparative SFC (column: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 5 μm);mobile phase: [Neu-EtOH]; B %: 20%-20%, min) to yield peak 1 and peak 2.Peak 1 was concentrated under reduced pressure to yield(5S)-3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(43.46 mg, 108.60 μmol, 33.6% yield, 100.0% purity, SFC: R_(t)=1.875,ee=100%, [α]^(33.3) _(D)=−156.346 (MeOH, c=0.053 g/100 mL)) as colorlessoil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.45-7.39 (m, 1H), 7.32 (d, J=8.1 Hz,2H), 7.15 (s, 1H), 7.12 (dd, J=1.4, 7.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H),6.93 (d, J=1.2 Hz, 1H), 5.62 (dd, J=9.3, 10.7 Hz, 1H), 3.59 (dd, J=10.8,17.2 Hz, 1H), 3.18 (dd, J=9.0, 17.2 Hz, 1H), 2.23 (s, 3H); ES-LCMS m/z399.9, 401.9 [M+H]⁺, 440.9, 442.9 [M+ACN+H]⁺. Peak 2 was concentratedunder reduced pressure to yield(5R)-3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(33.91 mg, 84.73 μmol, 26.2% yield, 100.0% purity, SFC: R_(t)=2.356,ee=100%, [α]^(33.2) _(D)=+141.289 (MeOH, c=0.091 g/100 mL)) as colorlessoil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.45-7.38 (m, 1H), 7.32 (d, J=7.9 Hz,2H), 7.15 (s, 1H), 7.12 (dd, J=1.4, 7.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H),6.93 (d, J=1.2 Hz, 1H), 5.62 (dd, J=9.2, 10.6 Hz, 1H), 3.59 (dd, J=11.0,17.2 Hz, 1H), 3.18 (dd, J=8.9, 17.2 Hz, 1H), 2.23 (s, 3H); ES-LCMS m/z399.9, 401.9 [M+H]⁺, 440.9, 442.9 [M+ACN+H]⁺.

I-84 & I-85

Step 1: 5-Bromo-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of 1-iodo-3-(trifluoromethyl)benzene (3.51 g, 12.90 mmol,1.86 mL, 1.2 eq) and 5-bromo-2-methyl-aniline (2 g, 10.75 mmol, 1 eq) intoluene (60 mL) was added Pd₂(dba)₃ (492.19 mg, 537.49 μmol, 0.05 eq),t-BuONa (1.03 g, 10.75 mmol, 1 eq) and BINAP (669.36 mg, 1.07 mmol, 0.1eq). The mixture was stirred at 120° C. for 2 h under N₂ atmosphere. Thereaction mixture was diluted with water (50 mL) then extracted withEtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and the filtrate was concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 2/1,TLC: PE/EtOAc=5/1, R_(f)=0.65) to yield5-bromo-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline (1.38 g, 2.80mmol, 26.1% yield, 67.1% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.00 (s, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.29 (d, J=1.7 Hz,1H), 7.20-7.17 (m, 1H), 7.16-7.12 (m, 3H), 7.10 (d, J=7.6 Hz, 1H), 2.15(s, 3H); ES-LCMS m/z 329.9, 332.0 [M+H]⁺.

Step 2: 2-Methyl-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline

To a solution of 5-bromo-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline(1.3 g, 2.64 mmol, 1 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (488.32 mg, 3.17 mmol,537.80 μL, 1.2 eq) in 1,4-dioxane (6 mL) and water (2 mL) was addedCs₂CO₃ (2.58 g, 7.93 mmol, 3 eq) and Pd(dppf)Cl₂ (193.33 mg, 264.22μmol, 0.1 eq). The mixture was bubbled with N₂ for 2 min then stirred at100° C. for 30 min under microwave (2 bar). The reaction mixture wasdiluted with water (150 mL) then extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=5/1, R_(f)=0.5) to yield2-methyl-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline (465 mg, 1.30mmol, 49.1% yield, 77.3% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.93 (s, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.29-7.28 (m, 1H),7.10 (d, J=7.6 Hz, 1H), 7.05-7.01 (m, 4H), 6.66 (d, J=10.9, 17.6 Hz,1H), 5.71 (d, J=17.5 Hz, 1H), 5.18 (d, J=11.0 Hz, 1H), 2.19 (s, 3H);ES-LCMS m/z 278.0 [M+H]⁺.

Step 3:5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]anilineand5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of 2-methyl-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline(300 mg, 836.33 μmol, 1 eq) and dibromomethanone oxime (305.34 mg, 1.51mmol, 1.8 eq) in EtOAc (30 mL) was added NaHCO₃ (702.60 mg, 8.36 mmol,325.28 μL, 10 eq). The mixture was stirred at 25° C. for 12 h under N₂atmosphere. The reaction mixture was diluted with water (50 mL) thenextracted with EtOAc (50 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=5/1, R_(f)=0.5) to yield thecompound which was separated by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30 mm, 5 um); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 25%-25%, min) toyield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressureto yield a residue which was lyophilized to yield5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline(15.27 mg, 36.49 μmol, 4.4% yield, 95.4% purity, SFC: R_(t)=1.156 min,ee=98.3%, [α]^(33.4) _(D)=+92.0, MeOH, c=0.05 g/100 mL) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.96 (s, 1H), 7.38 (t, J=7.8 Hz, 1H),7.27 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.10-6.96 (m, 4H), 5.68-5.59 (m,1H), 3.74 (d, J=10.9, 17.5 Hz, 1H), 3.27-3.21 (m, 1H), 2.19 (s, 3H);ES-LCMS m/z 400.9, 403.0 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was lyophilized to yield5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline(24.68 mg, 59.04 μmol, 7.1% yield, 95.5% purity, SFC: R_(t)=0.987 min,ee=99.7%, [α]^(33.4) _(D)=−137.8, MeOH, c=0.09 g/100 mL) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.96 (s, 1H), 7.38 (t, J=7.7 Hz, 1H),7.27 (d, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.12-6.97 (m, 4H), 5.72-5.57 (m,1H), 3.74 (d, J=11.0, 17.6 Hz, 1H), 3.27-3.21 (m, 1H), 2.19 (s, 3H);ES-LCMS m/z 400.9, 403.0 [M+H]⁺.

I-37

Step 1: 7-Nitro-1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinoline

To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (300 mg, 1.68 mmol,1 eq) and 1-iodo-3-(trifluoromethyl) benzene (457.95 mg, 1.68 mmol,242.30 μL, 1 eq) in toluene (10 mL) were added Cs₂CO₃ (1.10 g, 3.37mmol, 2 eq), XPhos (160.52 mg, 336.72 μmol, 0.2 eq) and Pd (OAc)₂ (37.80mg, 168.36 μmol, 0.1 eq) under N₂. The mixture was stirred at 100° C.for 12 h. TLC (PE/EtOAc=5/1, R_(f)=0.44) indicated the starting materialwas consumed completely and one new spot formed. The mixture wasconcentrated and sat.aq.NaHCO₃ (40 mL) was added. The mixture wasextracted with EtOAc (40 mL×3), concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(From PE/EtOAc=1/0 to 5/1, R_(f)=0.44) to yield7-nitro-1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinoline (180 mg,558.52 μmol, 33.2% yield, 100% purity) as a light yellow solid. ES-LCMSm/z 323.0 [M+H]⁺.

Step 2: 1-[3-(Trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-amine

To a solution of7-nitro-1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinoline (180 mg,558.52 μmol, 1 eq) in MeOH (10 mL) was added Pd/C (100 mg, 10%) underN₂. The mixture was stirred at 25° C. for 12 h under H₂ (30 psi). Thereaction mixture was filtered and the filtrate was concentrated to yield1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-amine (150 mg,crude) which was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.56-7.26 (m, 6H), 6.73 (d, J=7.4 Hz, 1H),6.12-6.02 (m, 2H), 3.56-3.52 (m, 2H), 2.61-2.58 (m, 2H), 1.88-1.83 (m,2H); ES-LCMS m/z 293.0 [M+H]⁺.

Step 3:N-[1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-yl]prop-2-enamide

To a solution of1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-amine (150 mg,513.17 μmol, 1 eq) in THE (5 mL) was added TEA (155.78 mg, 1.54 mmol,214.28 μL, 3 eq) and prop-2-enoyl chloride (55.74 mg, 615.81 μmol, 50.21μL, 1.2 eq) at 0° C. under N₂. The mixture was stirred at 25° C. for 1h. The reaction mixture was concentrated under reduced pressure to yielda residue which was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 50%-80%, 10 min), followed by lyophilization toyieldN-[1-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-quinolin-7-yl]prop-2-enamide(19.23 mg, 55.52 μmol, 10.8% yield, 100% purity) as a brown solid. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.50-7.43 (m, 3H), 7.30 (s, 1H), 7.09 (s,1H), 7.06-6.98 (m, 2H), 6.38-6.17 (m, 2H), 5.66 (dd, J=2.1, 9.7 Hz, 1H),3.67-3.59 (m, 2H), 2.79 (t, J=6.5 Hz, 2H), 2.01 (q, J=6.1 Hz, 2H);ES-LCMS m/z 346.9 [M+H]⁺.

I-38

Step 1: N-(3-bromophenyl)prop-2-enamide

To a solution of 3-bromoaniline (1 g, 5.81 mmol, 632.91 μL, 1 eq) in DCM(15 mL) was added TEA (1.18 g, 11.63 mmol, 1.62 mL, 2 eq) andprop-2-enoyl chloride (578.76 mg, 6.39 mmol, 521.40 μL, 1.1 eq) underN₂. The mixture was stirred at 25° C. for 1 h. TLC (PE/EtOAc=5/1,R_(f)=0.22) indicated the starting material was consumed completely andone new spot formed. The reaction mixture was concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (From PE/EtOAc=1/0 to 5/1, R_(f)=0.22) to yieldN-(3-bromophenyl) prop-2-enamide (1.2 g, 5.20 mmol, 89.5% yield, 98.0%purity) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85 (s, 1H),7.48 (d, J=7.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.22-7.17 (m, 1H), 6.45 (dd,J=1.2, 16.8 Hz, 1H), 6.23 (dd, J=10.4, 17.0 Hz, 1H), 5.81 (dd, J=1.2,10.2 Hz, 1H); ES-LCMS m/z 225.9, 227.8 [M+H]⁺.

Step 2:N-[3-[7-(trifluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]phenyl]prop-2-enamide

A mixture of N-(3-bromophenyl)prop-2-enamide (200 mg, 884.68 μmol, 1eq), 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (177.99 mg, 884.68μmol, 1 eq), Ruphos (82.57 mg, 176.94 μmol, 0.2 eq), Pd₂(dba)₃ (81.01mg, 88.47 μmol, 0.1 eq) and t-BuONa (170.04 mg, 1.77 mmol, 2 eq) intoluene (10 mL) was degassed and purged with N₂ for three times. Themixture was stirred at 100° C. for 12 h under N₂ atmosphere. The mixturewas concentrated and sat.aq. NaHCO₃ (40 mL) was added. The mixture wasextracted with EtOAc (40 mL×3), concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(From PE/EtOAc=1/0 to 5/1, R_(f)=0.58) and preparative HPLC (column:Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.04% NH₃H₂O10 mM NH₄HCO₃)-ACN]; B %: 52%-82%, 10 min), followed by lyophilizationto yieldN-[3-[7-(trifluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]phenyl]prop-2-enamide(12.89 mg, 37.22 μmol, 4.2% yield, 100.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.56 (s, 1H), 7.35-7.28 (m, 2H), 7.11 (d,J=7.8 Hz, 1H), 7.02 (d, J=6.7 Hz, 1H), 6.95-6.88 (m, 2H), 6.44 (d,J=16.0 Hz, 1H), 6.29-6.19 (m, 1H), 5.79 (d, J=11.3 Hz, 1H), 3.68-3.62(m, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.08-2.01 (m, 2H); ES-LCMS m/z 347.0[M+H]⁺.

I-86 & I-87

Step 1: 6-Bromo-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine

To a solution of 6-bromo-3-methyl-pyridin-2-amine (1 g, 5.35 mmol, 1 eq)and [3-(trifluoromethyl)phenyl]boronic acid (1.52 g, 8.02 mmol, 1.5 eq)in DCM (20 mL) was added Cu(OAc)₂ (1.94 g, 10.69 mmol, 2 eq) and DIEA(2.07 g, 16.04 mmol, 2.79 mL, 3 eq). The mixture was stirred at 25° C.for 12 h under O₂ atmosphere (15 psi). The reaction mixture was filteredthrough a pad of celite and the filtrate was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=3/1, R_(f)=0.65) to yield6-bromo-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine (861 mg,2.60 mmol, 48.6% yield, 100.0% purity) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.47 (s, 1H), 8.12 (s, 1H), 7.97 (d, J=8.5 Hz, 1H),7.51 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H),6.99 (d, J=7.6 Hz, 1H), 2.27-2.22 (m, 3H); ES-LCMS m/z 331.0, 332.9[M+H]⁺.

Step 2: 3-Methyl-N-[3-(trifluoromethyl)phenyl]-6-vinyl-pyridin-2-amine

To a solution of6-bromo-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine (800 mg,2.42 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(446.51 mg, 2.90 mmol, 491.75 μL, 1.2 eq) in water (0.5 mL) and1,4-dioxane (1.5 mL) was added Pd(dppf)Cl₂ (176.78 mg, 241.60 μmol, 0.1eq) and Cs₂CO₃ (2.36 g, 7.25 mmol, 3 eq). The mixture was bubbled withN₂ for 2 min then stirred at 80° C. for 1 h under microwave. Thereaction mixture was filtered through a pad of celite and the filtratewas concentrated to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=5/1,R_(f)=0.70) to yield3-methyl-N-[3-(trifluoromethyl)phenyl]-6-vinyl-pyridin-2-amine (267 mg,915.36 μmol, 37.9% yield, 95.4% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.50 (s, 1H), 8.27 (s, 1H), 7.98 (d, J=8.4 Hz, 1H),7.52-7.44 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.70(dd, J=10.6, 17.2 Hz, 1H), 6.12 (dd, J=1.9, 17.2 Hz, 1H), 5.33 (dd,J=1.8, 10.5 Hz, 1H), 2.29 (s, 3H); ES-LCMS m/z 279.0 [M+H]⁺.

Step 3:6-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine&6-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine

To a solution of3-methyl-N-[3-(trifluoromethyl)phenyl]-6-vinyl-pyridin-2-amine (200 mg,684.22 μmol, 1 eq) and dibromomethanone oxime (208.17 mg, 1.03 mmol, 1.5eq) in EtOAc (10 mL) was added NaHCO₃ (574.79 mg, 6.84 mmol, 10 eq). Themixture was stirred at 25° C. for 12 h under N₂ atmosphere. The reactionmixture was diluted with water (50 mL) then extracted with EtOAc (30mL×3). The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated to yield a residue which was purified byflash silica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=3/1, R_(f)=0.75) to yield the compound which was separated bySFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, Sum); mobile phase:[0.1% NH₃H₂O/EtOH]; B %: 30%-30%) to yield Peak 1 and Peak 2. Peak 1 wasconcentrated under reduced pressure to yield a residue which waslyophilized to yield6-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine(56.51 mg, 141.21 μmol, 20.6% yield, 100.0% purity, SFC: R_(t)=3.042min, ee=96.9%, [α]^(30.5) _(D)+120 (MeOH, c=0.055 g/100 mL)) as a whitesolid; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.34 (s, 1H), 8.11 (s, 1H), 8.03(d, J=8.1 Hz, 1H), 7.54-7.44 (m, 2H), 7.22 (d, J=7.8 Hz, 1H), 6.89 (d,J=7.3 Hz, 1H), 5.62 (dd, J=7.9, 10.8 Hz, 1H), 3.72-3.64 (m, 1H),3.60-3.53 (m, 1H), 2.29 (s, 3H); ES-LCMS m/z 399.9, 402.0 [M+H]⁺. Peak 2was concentrated under reduced pressure to yield a residue which waslyophilized to yield6-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-3-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine(53.58 mg, 133.89 μmol, 19.6% yield, 100.0% purity, SFC: R_(t)=3.264min, ee=94.8%, [α]^(30.5) _(D)=−118.52 (MeOH, c=0.054 g/100 mL)) as awhite solid; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.34 (s, 1H), 8.12 (s, 1H),8.03 (d, J=8.2 Hz, 1H), 7.56-7.43 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 6.90(d, J=7.3 Hz, 1H), 5.62 (dd, J=7.9, 10.8 Hz, 1H), 3.72-3.65 (m, 1H),3.61-3.54 (m, 1H), 2.30 (s, 3H); ES-LCMS m/z 400.0, 401.9 [M+H]⁺.

I-39

Step 1: 3-Bromo-5-methoxy-aniline

To a solution of 1-bromo-3-methoxy-5-nitro-benzene (10 g, 43.10 mmol, 1eq) in THE (80 mL), H₂O (80 mL) and EtOH (80 mL) was added Fe (24.07 g,430.98 mmol, 10 eq) and NH₄Cl (23.05 g, 430.98 mmol, 10 eq). The mixturewas stirred at 55° C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.4) showedstarting material was consumed completely and one major new spot wasdetected. The mixture was filtered and the filtrate was concentrated toyield a residue which was purified by flash silica gel chromatography(from pure PE to PE/EtOAc=2/1, TLC: PE/EtOAc=3/1, R_(f)=0.4) to yield3-bromo-5-methoxy-aniline (6.7 g, 29.84 mmol, 69.3% yield, 90.0% purity)as a gray solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 6.33 (t, J=2.0 Hz, 1H),6.22 (t, J=2.0 Hz, 1H), 6.09 (t, J=2.0 Hz, 1H), 5.39 (s, 2H), 3.68-3.62(m, 3H); ES-LCMS m/z 201.9, 203.9 [M+H]⁺, 242.9, 244.9 [M+ACN+H]⁺.

Step 2: 7-Bromo-5-methoxy-quinoline and 5-bromo-7-methoxy-quinoline

To a solution of 3-bromo-5-methoxy-aniline (5.7 g, 25.39 mmol, 1 eq) inH₂SO₄ (46.00 g, 351.75 mmol, 25 mL, 13.85 eq) was added glycerol (5.85g, 63.47 mmol, 4.75 mL, 2.5 eq) and nitrobenzene (3.75 g, 30.47 mmol,3.13 mL, 1.2 eq). The mixture was stirred at 150° C. for 3 h. TLC(PE/EtOAc=3/1, P1: R_(f)=0.60, P2: R_(f)=0.35) showed starting materialwas consumed completely and a lot of new spots were detected. To themixture was added 100 g crushed ice, EtOAc (100 mL) and 15% solution ofNaOH (30 mL). The mixture was stirred at 25° C. for 1 h. The mixture wasfiltered and the filtrate was extracted with EtOAc (60 mL×3). Thecombine organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from pure PE toPE/EtOAc=4/1, TLC: PE/EtOAc=3/1, P1: R_(f)=0.60, P2: R_(f)=0.35) toyield 7-bromo-5-methoxy-quinoline (650 mg, 2.46 mmol, 9.7% yield, 90.0%purity) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.91 (dd,J=1.7, 4.1 Hz, 1H), 8.48 (dd, J=0.9, 8.4 Hz, 1H), 7.79 (d, J=0.6 Hz,1H), 7.54 (dd, J=4.2, 8.5 Hz, 1H), 7.20 (d, J=1.5 Hz, 1H), 4.01 (s, 3H);ES-LCMS m/z 237.9, 239.9 [M+H]⁺. And 5-bromo-7-methoxy-quinoline (1.3 g,4.37 mmol, 17.2% yield, 80.0% purity) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.88 (dd, J=1.5, 4.5 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 7.67 (d, J=2.5 Hz, 1H), 7.52 (dd, J=4.5, 8.4 Hz, 1H), 7.46 (d,J=2.5 Hz, 1H), 3.93 (s, 3H); ES-LCMS m/z 237.9, 239.9 [M+H]⁺.

Step 3: 5-Bromoquinolin-7-ol

A solution of 5-bromo-7-methoxy-quinoline (1.3 g, 4.37 mmol, 1 eq) inHBr (37.25 g, 220.98 mmol, 25 mL, 48% purity, 50.59 eq) was stirred at110° C. for 12 h. The reaction mixture was concentrated to yield aresidue. To the residue was added EtOAc (50 mL) and saturated NaHCO₃ (60mL, adjust pH to 8). The mixture was filtered and the filtered cake wasconcentrated to yield the product, the filtrate was extracted with EtOAc(60 mL×3). The combine organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by flash silica gel chromatography (from pure PE toEtOAc/MeOH=10/1, TLC: PE/EtOAc=1/1, R_(f)=0.40) to yield5-bromoquinolin-7-ol (800 mg, 3.21 mmol, 73.6% yield, 90.0% purity) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.64 (dd, J=1.5, 4.1 Hz,1H), 8.18 (d, J=8.0 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.21 (dd, J=4.5,8.5 Hz, 1H), 7.05 (s, 1H); ES-LCMS m/z 223.8, 225.8 [M+H]⁺.

Step 4: 5-Bromo-7-[3-(trifluoromethyl)phenoxy]quinoline

To a mixture of 5-bromoquinolin-7-ol (300 mg, 1.21 mmol, 1 eq) and1-iodo-3-(trifluoromethyl)benzene (327.79 mg, 1.21 mmol, 173.43 μL, 1eq) in DMSO (2 mL) was added pyridine-2-carboxylic acid (14.84 mg,120.51 μmol, 0.1 eq), K₃PO₄ (409.27 mg, 1.93 mmol, 1.6 eq) and CuI(22.95 mg, 120.51 μmol, 0.1 eq). The mixture was stirred at 120° C. for12 h under N₂ atmosphere. TLC (PE/EtOAc=3/1, R_(f)=0.65) showed startingmaterial was consumed and one major new spot was detected. The mixturewas filtered and the filtrate was diluted with H₂O (50 mL) and extractedwith EtOAc (60 mL×3). The combine organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated to yield a residue which waspurified by flash silica gel chromatography (from pure PE toPE/EtOAc=5/1, TLC: PE/EtOAc=3/1, R_(f)=0.65) to yield5-bromo-7-[3-(trifluoromethyl)phenoxy]quinoline (200 mg, 488.93 μmol,40.6% yield, 90.0% purity) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 8.96-8.84 (m, 1H), 8.53-8.32 (m, 1H), 8.10-7.88 (m, 1H), 7.75-7.68(m, 1H), 7.67-7.57 (m, 3H), 7.54-7.48 (m, 1H), 7.44 (d, J=2.0 Hz, 1H).

Step 5: (E)-3-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]prop-2-enamide

To a mixture of 5-bromo-7-[3-(trifluoromethyl)phenoxy]quinoline (200 mg,488.93 μmol, 1 eq) and prop-2-enamide (173.76 mg, 2.44 mmol, 168.70 μL,5 eq) in 1,4-dioxane (10 mL) was added Cs₂CO₃ (477.91 mg, 1.47 mmol, 3eq), Pd(OAc)₂ (10.98 mg, 48.89 μmol, 0.1 eq), XPhos (46.62 mg, 97.79μmol, 0.2 eq) under N₂ atmosphere. The mixture was stirred under N₂atmosphere at 120° C. in microwave (1 bar) for 2 h. The mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combineorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by preparative HPLC(column: YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 46%-66%, 10 min) andlyophilized to yield(E)-3-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]prop-2-enamide (30.13mg, 84.09 μmol, 17.2% yield, 100.0% purity) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.94-8.88 (m, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.41(d, J=15.5 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.50-7.47(m, 1H), 7.44 (dd, J=4.5, 8.6 Hz, 1H), 7.40 (s, 1H), 7.34-7.30 (m, 1H),6.55 (d, J=15.5 Hz, 1H), 5.61 (br s, 2H); ES-LCMS m/z 359.1 [M+H]⁺.

I-88 & I-89

Step 1: 2-Chloro-5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridine

A mixture of 4-bromo-2-chloro-5-methyl-pyridine (300 mg, 1.45 mmol, 1eq), 3-(trifluoromethyl)phenol (235.55 mg, 1.45 mmol, 174.48 μL, 1 eq),pyridine-2-carboxylic acid (17.89 mg, 145.30 μmol, 0.1 eq), K₃PO₄(616.85 mg, 2.91 mmol, 2 eq) and CuI (27.67 mg, 145.30 μmol, 0.1 eq) inDMSO (10 mL) was degassed and purged with N₂ for 3 times then themixture was stirred at 120° C. for 12 h under N₂ atmosphere. The mixturewas diluted with water (100 mL) then extracted with EtOAc (100 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.70) to yield2-chloro-5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridine (400 mg, 1.33mmol, 91.4% yield, 95.5% purity) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.30 (s, 1H), 7.76-7.65 (m, 2H), 7.62 (s, 1H), 7.51 (d,J=8.1 Hz, 1H), 6.71 (s, 1H), 2.24 (s, 3H); ES-LCMS m/z 287.9, 289.9[M+H]⁺.

Step 2: 5-Methyl-4-[3-(trifluoromethyl)phenoxy]-2-vinyl-pyridine

To a solution of2-chloro-5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridine (350 mg, 1.16mmol, 1 eq) in 1,4-dioxane (12 mL) and water (2 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (214.75 mg, 1.39 mmol,236.51 μL, 1.2 eq), Pd(dppf)Cl₂ (85.02 mg, 116.19 μmol, 0.1 eq) andCs₂CO₃ (1.14 g, 3.49 mmol, 3 eq). The mixture was bubbled with N₂ for 2min and stirred at 100° C. for 30 min under microwave. The mixture wasdiluted with water (100 mL) then extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.70) to yield5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-vinyl-pyridine (300 mg, 1.02mmol, 87.8% yield, 95% purity) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.44 (s, 1H), 7.71-7.66 (m, 1H), 7.63-7.59 (m, 1H), 7.49(s, 1H), 7.41 (d, 8.1 Hz, 1H), 6.86 (s, 1H), 6.71 (dd, J=10.8, 17.4 Hz,1H), 6.12 (dd, J=1.7, 17.4 Hz, 1H), 5.37 (dd, J=1.7, 10.8 Hz, 1H), 2.23(s, 3H); ES-LCMS m/z 280.0 [M+H]⁺.

Step 3:(5R)-3-bromo-5-[5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole&(5S)-3-bromo-5-[5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole

A mixture of 5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-vinyl-pyridine(250 mg, 850.47 μmol, 1 eq), dibromomethanone oxime (345.01 mg, 1.70mmol, 2 eq), NaHCO₃ (714.45 mg, 8.50 mmol, 10 eq) in EtOAc (10 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 25° C. for 12 h under N₂ atmosphere. The mixture was dilutedwith water (100 mL) then extracted with EtOAc (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.65) to yield a residuewhich was separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm,5 μm); mobile phase: [0.1% NH₃.H₂O EtOH]; B %: 10%-10%, min) to yieldPeak 1 and Peak 2. Peak 1 was concentrated under reduced pressure toyield a residue which was lyophilized to yield(5S)-3-bromo-5-[5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole(31.67 mg, 77.84 μmol, 9.2% yield, 98.6% purity, SFC: R_(t)=0.511,ee=100%; [α]^(30.4) _(D)=+210.1, MeOH, c=0.159 g/100 mL) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.48 (s, 1H), 7.75-7.68 (m, 1H),7.68-7.63 (m, 1H), 7.55 (s, 1H), 7.46 (d, J=8.2 Hz, 1H), 6.79 (s, 1H),5.65 (dd, J=7.4, 11.0 Hz, 1H), 3.73-3.65 (m, 1H), 3.60-3.50 (m, 1H),2.27 (s, 3H); ES-LCMS m/z 400.9, 402.9 [M+H]⁺. Peak 2 was concentratedunder reduced pressure to yield a residue which was lyophilized to yield(5R)-3-bromo-5-[5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole(19.39 mg, 48.33 μmol, 5.9% yield, 100% purity, SFC: R_(t)=0.417,ee=100%; [α]^(30.4) _(D)=−214.7, MeOH, c=0.109 g/100 mL) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (s, 1H), 7.75-7.69 (m, 1H),7.68-7.63 (m, 1H), 7.56 (s, 1H), 7.46 (d, J=8.2 Hz, 1H), 6.80 (s, 1H),5.66 (dd, J=7.4, 11.0 Hz, 1H), 3.74-3.65 (m, 1H), 3.59-3.51 (m, 1H),2.27 (s, 3H); ES-LCMS m/z 400.9, 402.9 [M+H]⁺.

I-141 & I-142

Step 1: Tert-butyl4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-vinylpiperidine-1-carboxylate (1 g, 4.73mmol, 1 eq) in EtOAc (20 mL) was added NaHCO₃ (3.98 g, 47.33 mmol, 10eq) and dibromomethanone oxime (1.44 g, 7.10 mmol, 1.5 eq). The mixturewas stirred at 25° C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.95) showedstarting material was remained and one new spot was detected. Themixture was diluted with water (100 mL) then extracted with EtOAc (100mL×3). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.5) to yieldtert-butyl 4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate(1 g, 2.70 mmol, 57.0% yield, 90% purity) as yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.52-4.40 (m, 1H), 4.01-3.91 (m, 2H), 3.29 (d,J=10.5 Hz, 1H), 3.10 (dd, J=8.6, 17.6 Hz, 1H), 2.67 (d, J=1.7 Hz, 2H),1.74-1.62 (m, 2H), 1.56-1.45 (m, 1H), 1.38 (s, 9H), 1.11-0.97 (m, 2H).

Step 2: 3-Bromo-5-(4-piperidyl)-4,5-dihydroisoxazole

To a stirred solution of tert-butyl4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (900 mg,2.43 mmol, 1 eq) in TFA (9 mL) was added DCM (27 mL). The reactionmixture was stirred at 25° C. for 1 h. TLC (PE/EtOAc=3:1, R_(f)=0.00)showed starting material was remained and one new spot was detected. Thefiltrate was concentrated under reduced pressure to yield3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (930 mg, 2.41 mmol, 99.2%yield, 90% purity, TFA) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.57 (s, 1H), 4.58-4.39 (m, 1H), 3.26 (d, J=12.2 Hz, 2H), 2.86-2.74(m, 2H), 1.86-1.71 (m, 2H), 1.66 (d, J=13.9 Hz, 1H), 1.44-1.26 (m, 3H).

Step 3:(5R)-3-Bromo-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole&(5S)-3-bromo-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole

A mixture of 3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (800 mg, 2.07mmol, 1 eq, TFA), 1-(bromomethyl)-4-(trifluoromethyl)benzene (495.79 mg,2.07 mmol, 319.87 μL, 1 eq), TEA (1.26 g, 12.44 mmol, 1.73 mL, 6 eq) inTHE (12 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 25° C. for 12 h under N₂ atmosphere. The filtratewas concentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 1/1,TLC: PE/EtOAc=1/1, R_(f)=0.80) to yield the compound which was separatedby SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase:[0.1% NH₃H₂O EtOH]; B %: 15%-15%, min) to yield Peak 1 and Peak 2. Peak1 was concentrated under reduced pressure to yield a residue which waslyophilized to yield(5R)-3-bromo-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(66.08 mg, 168.91 μmol, 8.2% yield, 100% purity, SFC: R_(t)=2.565 min,ee=100%; [α]^(30.4) _(D)=+97.9, MeOH, c=0.049 g/100 mL) as yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1Hz, 2H), 4.49-4.36 (m, 1H), 3.54-3.45 (m, 2H), 3.29-3.22 (m, 2H), 3.04(dd, J=8.8, 17.6 Hz, 1H), 2.77 (d, J=11.2 Hz, 2H), 1.93-1.80 (m, 2H),1.65 (d, J=12.7 Hz, 1H), 1.53-1.39 (m, 2H), 1.20 (dd, J=3.5, 12.1 Hz,1H); ES-LCMS m/z 390.9, 392.9 [M+H]⁺. Peak 1 was concentrated underreduced pressure to yield a residue which was lyophilized to yield(5S)-3-bromo-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(67.11 mg, 171.54 μmol, 8.3% yield, 100% purity, SFC: R_(t)=2.666 min,ee=99.88%; [α]^(30.3) _(D)=−102.0, MeOH, c=0.049 g/100 mL) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.67 (d, J=8.2 Hz, 2H), 7.52 (d,J=7.8 Hz, 2H), 4.50-4.41 (m, 1H), 3.53 (s, 2H), 3.32-3.27 (m, 2H), 3.07(dd, J=8.6, 17.6 Hz, 1H), 2.81 (d, J=10.6 Hz, 2H), 1.96-1.87 (m, 2H),1.68 (d, J=12.1 Hz, 1H), 1.50 (d, J=12.9 Hz, 2H), 1.31-1.23 (m, 1H);ES-LCMS m/z 390.9, 392.9 [M+H]⁺.

I-40

Step 1:N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide

A mixture ofN-[4-bromo-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide (500 mg,1.17 mmol, 1 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(450.00 mg, 1.77 mmol, 1.52 eq), KOAc (450.00 mg, 4.59 mmol, 3.92 eq)and Pd(dppf)Cl₂ (45.00 mg, 61.50 μmol, 5.26e-2 eq) in 1,4-dioxane (10mL) was stirred under N₂ atmosphere at 90° C. for 12 h. TLC(PE/EtOAc=1/1, R_(f)=0.49) showed the starting material was consumedcompletely. The reaction mixture was concentrated under reduced pressureto yield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=1/1, R_(f)=0.49) to yieldN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide(160 mg, 333.15 μmol, 28.5% yield, 90.0% purity) as a colorless gum. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.89 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.60(br s, 1H), 7.47-7.42 (m, 2H), 7.38 (s, 1H), 7.23 (br d, J=7.3 Hz, 1H),7.17 (br s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.43 (d, J=17.5 Hz, 1H), 6.22(dd, J=10.6, 16.7 Hz, 1H), 5.78 (d, J=10.1 Hz, 1H), 1.37 (s, 12H);ES-LCMS m/z 433.1 [M+H]⁺.

Step 2:N-[4-(1-Methylimidazol-4-yl)-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide

A mixture ofN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide(50 mg, 104.11 μmol, 1 eq), 4-iodo-1-methylimidazole (25 mg, 120.19μmol, 1.15 eq), Cs₂CO₃ (115 mg, 352.96 μmol, 3.39 eq) and Pd(dppf)Cl₂(15 mg, 20.50 μmol, 1.97e-1 eq) in 1,4-dioxane (1.5 mL) and H₂O (0.5 mL)was bubbled with N₂ for 2 minutes and sealed. The reaction mixture wasirradiated under microwave (1 bar) at 100° C. for 0.5 h. The reactionwas carried out 3 times in parallel. The reaction mixture wasconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=20/1 to 1/1,TLC: PE/EtOAc=1/1, R_(f)=0.25). The desired fraction was concentratedunder reduced pressure to yield a residue which was purified bypreparative HPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobilephase: [water (0.04% NH₃.H₂O+10 mM NH₄HCO₃)-ACN]; B %: 41%-71%, 10 min).The desired fraction was lyophilized to yieldN-[4-(1-methylimidazol-4-yl)-3-[3-(trifluoromethyl)anilino]phenyl]prop-2-enamide(10.29 mg, 26.63 μmol, 8.5% yield, 100.0% purity) as a white solid. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 10.22 (s, 1H), 10.12 (s, 1H), 7.83 (d,J=1.8 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.56 (d, J=1.1 Hz,1H), 7.50-7.46 (m, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.24 (dd,J=2.1, 8.5 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.48-6.35 (m, 1H), 6.24 (dd,J=2.0, 16.9 Hz, 1H), 5.75 (dd, J=1.9, 10.1 Hz, 1H), 3.71 (s, 3H);ES-LCMS m/z 387.0 [M+H]⁺.

I-143

Step 1: tert-Butyl (3S)-3-formylpiperidine-1-carboxylate

To a solution of tert-butyl(3S)-3-(hydroxymethyl)piperidine-1-carboxylate (1.00 g, 4.64 mmol, 1 eq)in DCM (10 mL) was added DESS-MARTIN PERIODINANE (2.17 g, 5.11 mmol, 1.1eq). The mixture was stirred at 25° C. for 4 h. TLC (PE/EtOAc=2/1,R_(f)=0.70) showed the starting material was consumed completely. Thereaction mixture was diluted with H₂O (50 mL) and filtered. The filtratewas extracted with DCM (50 mL×3). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 5/1, TLC: PE/EtOAc=2/1, R_(f)=0.70) to yieldtert-butyl (3S)-3-formylpiperidine-1-carboxylate (400 mg, 1.78 mmol,38.4% yield, 95.0% purity) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δppm 9.71 (s, 1H), 4.00-3.90 (m, 1H), 3.70-3.60 (m, 1H), 3.33 (dd, J=8.2,13.6 Hz, 1H), 3.09 (ddd, J=3.3, 9.5, 13.1 Hz, 1H), 2.50-2.40 (m, 1H),2.00-1.90 (m, 1H), 1.72-1.65 (m, 2H), 1.56-1.50 (m, 1H), 1.47 (s, 9H).

Step 2: tert-Butyl (3R)-3-vinylpiperidine-1-carboxylate

To a solution of methyl(triphenyl)phosphonium; bromide (800 mg, 2.24mmol, 1.26 eq) in THE (10 mL) was added n-BuLi (2.5 M, 0.9 mL, 1.26 eq)dropwise under N₂ atmosphere at −78° C. The mixture was warmed to 0° C.and stirred under N₂ atmosphere at 0° C. for 0.5 h. The mixture wascooled to −78° C. and a solution of tert-butyl(3S)-3-formylpiperidine-1-carboxylate (400 mg, 1.78 mmol, 1 eq) in THE(5 mL) was added. The mixture was warmed to 25° C. and stirred under N₂atmosphere at 25° C. for 4 h. TLC (PE/EtOAc=5/1, R_(f)=0.50) showed thestarting material was consumed completely. The reaction mixture wasdiluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 8/1, TLC: PE/EtOAc=5/1,R_(f)=0.50) to yield tert-butyl (3R)-3-vinylpiperidine-1-carboxylate(350 mg, 1.66 mmol, 93.0% yield, N/A purity) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 5.72 (ddd, J=6.5, 10.7, 17.3 Hz, 1H), 5.14-4.96(m, 2H), 3.96 (d, J=13.3 Hz, 2H), 2.73 (ddd, J=3.1, 11.5, 13.1 Hz, 1H),2.60-2.50 (m, 1H), 2.23-2.11 (m, 1H), 1.91-1.82 (m, 1H), 1.72-1.63 (m,2H), 1.54-1.50 (m, 1H), 1.46 (s, 9H).

Step 3: tert-Butyl(3S)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylateand tert-butyl(3S)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate

A mixture of tert-butyl (3R)-3-vinylpiperidine-1-carboxylate (200 mg,946.52 μmol, 1 eq), dibromomethanone oxime (230.00 mg, 1.13 mmol, 1.2eq) and NaHCO₃ (795.17 mg, 9.47 mmol, 10 eq) in EtOAc (10 mL) wasstirred under N₂ atmosphere at 25° C. for 12 h. TLC (PE/EtOAc=4/1,R_(f)=0.35, 0.30) showed the starting material was consumed completely.The reaction mixture was diluted with H₂O (50 mL) and extracted withEtOAc (50 mL×3). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 5/1,TLC: PE/EtOAc=4/1, R_(f)=0.35, 0.30) to yield tert-butyl(3S)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate(130 mg, 388.18 μmol, 41.0% yield, 99.5% purity, SFC: R_(t)=2.246,Dr=99.84%) as a white solid and tert-butyl(3S)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate(160 mg, 478.24 μmol, 50.5% yield, 99.6% purity, SFC: R_(t)=2.346,Dr=94.44%) as a colorless gum.

tert-butyl(3S)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate:¹H NMR (400 MHz, CDCl₃) δ ppm 4.51 (d, J=7.8 Hz, 1H), 3.84 (d, J=8.6 Hz,2H), 3.27 (dd, J=10.6, 17.2 Hz, 1H), 3.00 (dd, J=9.2, 17.0 Hz, 1H),2.95-2.86 (m, 1H), 2.80-2.70 (m, 1H), 2.00-1.90 (m, 1H), 1.78-1.66 (m,2H), 1.46 (s, 9H), 1.45-1.37 (m, 2H); ES-LCMS m/z 276.9, 278.9[M-t-Bu+H]⁺.

tert-butyl(3S)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate:¹H NMR (400 MHz, CDCl₃) δ ppm 4.56-4.38 (m, 1H), 4.23-4.11 (m, 1H), 3.98(d, J=13.3 Hz, 1H), 3.22 (dd, J=10.6, 17.2 Hz, 1H), 2.99 (dd, J=9.4,16.8 Hz, 1H), 2.85-2.47 (m, 2H), 1.80-1.64 (m, 4H), 1.46 (s, 9H),1.33-1.26 (m, 1H); 276.9, 278.9 [M-t-Bu+H]⁺.

Step 4: (5R)-3-Bromo-5-[(3S)-3-piperidyl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3S)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate(130.00 mg, 388.18 μmol, 1 eq) in DCM (6 mL) was added TFA (3.06 g,26.88 mmol, 1.99 mL, 69.24 eq) dropwise. The mixture was stirred at 25°C. for 0.5 h. TLC (PE/EtOAc=4/1, R_(f)=0.06) showed the startingmaterial was consumed completely. The mixture was concentrated underreduced pressure to yield(5R)-3-bromo-5-[(3S)-3-piperidyl]-4,5-dihydroisoxazole (130 mg, 374.50μmol, 96.5% yield, TFA) as a colorless gum, which was used in the nextstep without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.15(s, 1H), 4.61 (d, J=11.7 Hz, 1H), 3.46-3.31 (m, 3H), 3.00 (dd, J=7.8,17.2 Hz, 1H), 2.90-2.80 (m, 2H), 2.20-2.10 (m, 1H), 2.08-2.00 (m, 2H),1.92-1.81 (m, 2H).

Step 5:(5R)-3-Bromo-5-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole

To a mixture of (5R)-3-bromo-5-[(3S)-3-piperidyl]-4,5-dihydroisoxazole(130 mg, 374.50 μmol, 1 eq, TFA) and DIEA (200.00 mg, 1.55 mmol, 269.54μL, 4.13 eq) in DCM (5 mL) was added1-(bromomethyl)-3-(trifluoromethyl)benzene (90 mg, 376.52 μmol, 57.32μL, 1.01 eq). The mixture was stirred at 25° C. for 12 h. The mixturewas concentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 49%-79%, 10 min). Thedesired fraction was lyophilized to yield a residue which was separatedby chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um);mobile phase: [0.1% NH₃.H₂O/EtOH]; B %: 15%-15%). The desired fractionwas concentrated under reduced pressure to yield(5R)-3-bromo-5-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole(56.21 mg, 143.68 μmol, 38.4% yield, 100.0% purity, SFC: R_(t)=2.439,Dr.=97.990%, [α]^(30.5) _(D)=+77.97 (CHCl₃, c=0.118 g/100 mL)) ascolorless oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.57 (s, 1H), 7.51 (dd,J=7.6, 12.5 Hz, 2H), 7.46-7.41 (m, 1H), 4.66-4.53 (m, 1H), 3.60-3.46 (m,2H), 3.15 (dd, J=10.5, 17.1 Hz, 1H), 2.91 (dd, J=9.2, 17.1 Hz, 1H), 2.70(d, J=10.8 Hz, 1H), 2.64 (d, J=9.5 Hz, 1H), 2.10 (t, J=10.1 Hz, 1H),2.01-1.94 (m, 1H), 1.88 (ttd, J=3.3, 6.5, 9.8 Hz, 1H), 1.83-1.72 (m,2H), 1.63-1.58 (m, 1H), 1.25 (d, J=12.4 Hz, 1H); ES-LCMS m/z 390.9,392.9 [M+H]⁺.

I-144

Step 1: (5S)-3-Bromo-5-[(3S)-3-piperidyl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3S)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]piperidine-1-carboxylate(160.00 mg, 478.24 μmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 56.48 eq) dropwise. The mixture was stirred at 25°C. for 0.5 h. TLC (PE/EtOAc=4/1, R_(f)=0.06) showed the startingmaterial was consumed completely. The mixture was concentrated underreduced pressure to yield(5S)-3-bromo-5-[(3S)-3-piperidyl]-4,5-dihydroisoxazole (160 mg, 460.92μmol, 96.4% yield, N/A purity, TFA) as a colorless gum, which was usedin the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 8.99 ((br s, 1H), 8.75 (br s, 1H), 4.63-4.46 (m, 1H), 3.60 (d,J=11.3 Hz, 1H), 3.46 (d, J=10.6 Hz, 1H), 3.33 (dd, J=10.4, 17.4 Hz, 1H),3.03 (dd, J=8.6, 17.2 Hz, 1H), 2.96-2.86 (m, 1H), 2.84-2.74 (m, 1H),2.24-2.14 (m, 1H), 2.02-1.81 (m, 3H).

Step 2:(5S)-3-Bromo-5-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole

To a mixture of (5S)-3-bromo-5-[(3S)-3-piperidyl]-4,5-dihydroisoxazole(160 mg, 686.39 μmol, 1 eq, TFA) and DIEA (355 mg, 2.75 mmol, 478.44 μL,4 eq) in DCM (5 mL) was added 1-(bromomethyl)-3-(trifluoromethyl)benzene(167 mg, 698.65 μmol, 106.37 μL, 1.02 eq). The mixture was stirred at25° C. for 12 h. The mixture was concentrated under reduced pressure toyield a residue which was purified by preparative HPLC (column: WelchXtimate C18 150*25 mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 49%-79%, 10 min). The desired fraction was lyophilized to yield aresidue which was purified by preparative TLC (PE/EtOAc=3/1,R_(f)=0.30). The crude product was separated by chiral SFC (column:DAICEL CHIRALCEL OJ-H (250 mm*30 mm, Sum); mobile phase: [0.1% NH₃.H₂OEtOH]; B %: 10%-10%). The desired fraction was concentrated underreduced pressure to yield(5S)-3-bromo-5-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole(19.81 mg, 50.64 μmol, 7.4% yield, 100.0% purity, SFC: R_(t)=2.089,Dr.=100.000%, [α]^(30.6) _(D)=−88.37 (CHCl₃, c=0.043 g/100 mL)) as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.57 (s, 1H), 7.51 (d, J=7.6Hz, 2H), 7.46-7.40 (m, 1H), 4.57-4.46 (m, 1H), 3.62-3.49 (m, 2H), 3.19(dd, J=10.4, 17.1 Hz, 1H), 3.04-2.91 (m, 2H), 2.73 (d, J=11.7 Hz, 1H),2.04-1.90 (m, 3H), 1.74-1.59 (m, 3H), 1.06 (d, J=7.5 Hz, 1H); ES-LCMSm/z 390.9, 392.9 [M+H]⁺.

I-90 & I-91

Step 1: 2-Methyl-5-vinyl-phenol

To a solution of 5-bromo-2-methyl-phenol (5 g, 26.73 mmol, 1 eq) in1,4-dioxane (6 mL) and H₂O (2 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (6.18 g, 40.10 mmol,6.80 mL, 1.5 eq), Pd(dppf)Cl₂ (1.96 g, 2.67 mmol, 0.1 eq) and Cs₂CO₃(26.13 g, 80.20 mmol, 3 eq). The mixture was bubbled with N₂ for 3 minand stirred at 80° C. for 30 min under microwave. To the mixture wasadded water (30 mL) and extracted with ethyl acetate (30 mL×3). Thecombined organic phase was washed with brine (20 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=200/1 to 5/1, TLC: PE/EtOAc=5/1, R_(f)=0.48) to yield2-methyl-5-vinyl-phenol (1.7 g, 11.91 mmol, 44.6% yield, 94% purity) asyellow oil.

¹H NMR (500 MHz, CD₃OD) δ ppm 6.99 (d, J=7.6 Hz, 1H), 6.82 (s, 1H), 6.78(d, J=7.6 Hz, 1H), 6.60 (dd, J=10.9, 17.6 Hz, 1H), 5.63 (d, J=17.7 Hz,1H), 5.10 (d, J=10.8 Hz, 1H), 2.16 (s, 3H); ES-LCMS m/z 135.0 [M+H]⁺.

Step 2: 2-(2-Methyl-5-vinyl-phenoxy)-4-(trifluoromethyl)pyridine

To a solution of 2-methyl-5-vinyl-phenol (700 mg, 4.90 mmol, 1 eq) and2-bromo-4-(trifluoromethyl)pyridine (919.88 mg, 4.07 mmol, 0.83 eq) inDMSO (20 mL) was added CuI (43.90 mg, 230.49 μmol, 0.047 eq),pyridine-2-carboxylic acid (48.30 mg, 392.32 umol, 0.08 eq) and K₃PO₄(1.74 g, 8.19 mmol, 1.67 eq). The mixture was stirred at 120° C. for 12h. To the mixture was added water (30 mL) and extracted with ethylacetate (30 mL×3). The combined organic phase was washed with brine (20mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=200/1 to 10/1, TLC: PE/EtOAc=10/1, R_(f)=0.35) to yield2-(2-methyl-5-vinyl-phenoxy)-4-(trifluoromethyl)pyridine (400 mg, 1.15mmol, 23.4% yield, 80% purity) as a yellow oil. ¹H NMR (500 MHz, CD₃OD)δ ppm 7.34 (s, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 7.26 (d, J=1.8 Hz, 1H),7.24 (s, 1H), 7.14 (s, 1H), 6.73-6.67 (m, 1H), 5.73 (d, J=17.5 Hz, 1H),5.21 (d, J=11.0 Hz, 1H), 2.11 (s, 3H); ES-LCMS m/z 280.0 [M+H]⁺.

Step 3:(5R)-3-Bromo-5-[4-methyl-3-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4,5-dihydroisoxazole(5S)-3-Bromo-5-[4-methyl-3-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4,5-dihydroisoxazole

To a solution of2-(2-methyl-5-vinyl-phenoxy)-4-(trifluoromethyl)pyridine (400 mg, 1.15mmol, 1 eq) and dibromomethanone oxime (464.85 mg, 2.29 mmol, 2 eq) inEtOAc (5 mL) was added NaHCO₃ (962.67 mg, 11.46 mmol, 10 eq). Themixture was stirred at 25° C. for 12 h under N₂ atmosphere. To themixture was added water (30 mL) and extracted with ethyl acetate (30mL×3). The combined organic phase was washed with brine (20 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to yield aresidue which was purified by preparative TLC (PE/EtOAc=3/1, R_(f)=0.40)to yield the product. The product was separated by SFC (column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3-H₂O ETOH]; B%: 30%-30%, min) to yield peak 1 and peak 2. Peak 1 was concentratedunder reduced pressure to yield a residue which was dissolved in MeCN(10 mL) and H₂O (20 mL) and lyophilized to yield(5R)-3-bromo-5-[4-methyl-3-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4,5-dihydroisoxazole(16.27 mg, 40.56 μmol, 3.5% yield, 100% purity, SFC: R_(t)=2.368 min,ee=100, [α]30.3_(D)=+13.423 (MeOH, c=0.0536 g/100 mL)) as a white solid.¹H NMR (400 MHz, CD₃OD) δ ppm 8.29 (d, J=5.5 Hz, 1H), 7.39-7.32 (m, 2H),7.29 (s, 1H), 7.20 (dd, J=1.6, 7.8 Hz, 1H), 7.09 (d, J=1.6 Hz, 1H), 5.68(dd, J=9.2, 10.8 Hz, 1H), 3.71 (dd, J=10.8, 17.4 Hz, 1H), 3.25 (dd,J=8.8, 17.4 Hz, 1H), 2.14 (s, 3H); ES-LCMS m/z 400.8, 402.8[M+H]⁺. Peak2 was concentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and H₂O (20 mL) and lyophilized to yield(5S)-3-bromo-5-[4-methyl-3-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4,5-dihydroisoxazole(15.43 mg, 38.46 μmol, 3.4% yield, 100% purity, R_(t)=4.567 min,ee=100%, [α]^(30.2) _(D)=−13.805 (MeOH, c=0.0565 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.29 (d, J=5.5 Hz, 1H), 7.38-7.33(m, 2H), 7.29 (s, 1H), 7.20 (dd, J=1.6, 7.8 Hz, 1H), 7.09 (d, J=1.6 Hz,1H), 5.69 (dd, J=9.2, 10.8 Hz, 1H), 3.71 (dd, J=10.8, 17.4 Hz, 1H), 3.25(dd, J=9.0, 17.6 Hz, 1H), 2.14 (s, 3H); ES-LCMS m/z 400.8, 402.8 [M+H]⁺.

I-49

Step 1:N-[1-[[2-(Trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide

A mixture of N-(4-piperidyl)prop-2-enamide (150 mg, 924.07 μmol, 1 eq),1-(bromomethyl)-2-(trifluoromethyl)benzene (220.88 mg, 924.07 μmol,140.69 μL, 1 eq), DIEA (238.86 mg, 1.85 mmol, 321.91 μL, 2 eq) in DCM (3mL) was stirred at 25° C. for 30 min under N₂ atmosphere. The solventwas removed to yield a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.04%NH₃H₂O*10 mM NH₄HCO₃)-ACN]; B %: 37%-67%, 10 min). The desired fractionwas lyophilized to yieldN-[1-[[2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide (74mg, 236.93 μmol, 25.6% yield, 100% purity) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.00 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H),7.71-7.62 (m, 2H), 7.49-7.42 (m, 1H), 6.25-6.16 (m, 1H), 6.10-6.02 (m,1H), 5.55 (dd, J=2.4, 10.0 Hz, 1H), 3.69-3.58 (m, 3H), 2.73 (d, J=11.5Hz, 2H), 2.10 (t, J=10.8 Hz, 2H), 1.75 (d, J=10.3 Hz, 2H), 1.49-1.37 (m,2H); ES-LCMS m/z 313.0 [M+H]⁺.

I-50

Step 1:N-[1-[4-(Trifluoromethyl)phenyl]sulfonyl-4-piperidyl]prop-2-enamide

To a solution of N-(4-piperidyl)prop-2-enamide (100 mg, 616.05 μmol, 1eq) in DCM (5 mL) was added DIEA (159.24 mg, 1.23 mmol, 214.60 μL, 2 eq)and 4-(trifluoromethyl)benzenesulfonyl chloride (452.09 mg, 1.85 mmol, 3eq). The mixture was stirred at 30° C. for 12 h. The reaction mixturewas concentrated to yield a residue which was purified by preparativeHPLC (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase:[water (0.05% HCl)-ACN]; B %: 41%-61%, 10 min) and lyophilized to yieldN-[1-[4-(trifluoromethyl)phenyl]sulfonyl-4-piperidyl]prop-2-enamide(51.67 mg, 137.67 μmol, 22.4% yield, 96.6% purity) as a white solid. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.09-8.00 (m, 3H), 7.99-7.94 (m, 2H),6.20-6.11 (m, 1H), 6.09-6.00 (m, 1H), 5.56 (dd, J=2.3, 10.1 Hz, 1H),3.70-3.60 (m, 1H), 3.54 (d, J=12.1 Hz, 2H), 2.62-2.56 (m, 2H), 1.83 (d,J=10.4 Hz, 2H), 1.49-1.36 (m, 2H); ES-LCMS m/z 363.0 [M+H]⁺, 385.0[M+Na]⁺.

I-51

Step 1:N-[1-[[3-(Trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide

To a solution of N-(4-piperidyl)prop-2-enamide (150 mg, 924.06 μmol, 1eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (220.88 mg, 924.06μmol, 140.69 μL, 1 eq) in DCM (10 mL) was added DIEA (238.86 mg, 1.85mmol, 321.91 μL, 2 eq). The mixture was stirred at 30° C. for 30 minunder N₂ atmosphere. The reaction mixture was concentrated to yield aresidue which was purified by preparative HPLC (column: Agela DuraShellC18 150*25 mm*5 um; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 30%-60%, 10 min). The desired fraction waslyophilized to yieldN-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide (60mg, 189.42 μmol, 20.5% yield, 98.6% purity) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.99 (d, J=7.6 Hz, 1H), 7.64-7.54 (m, 4H),6.24-6.16 (m, 1H), 6.09-6.02 (m, 1H), 5.58-5.53 (m, 1H), 3.66-3.57 (m,1H), 3.55 (s, 2H), 2.74 (d, J=11.7 Hz, 2H), 2.06 (t, J=10.6 Hz, 2H),1.74 (d, J=10.0 Hz, 2H), 1.47-1.35 (m, 2H); ES-LCMS m/z 313.0 [M+H]⁺.

P-8

Step 1:N-Methyl-3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzamide

To a stirred solution of3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzoic acid(100 mg, 247.73 μmol, 1 eq) in DCM (10 mL) was added methanamine;hydrochloride (25.09 mg, 371.60 μmol, 1.5 eq),[chloro(dimethylamino)methylene]-dimethyl-ammonium; hexafluorophosphate(104.26 mg, 371.60 μmol, 1.5 eq) and 1-methylimidazole (61.02 mg, 743.20μmol, 59.24 μL, 3 eq). The reaction mixture was stirred at 29° C. for 6h. The reaction mixture was concentrated to yield a residue which waspurified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5um; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %:40%-70%, 10 min). The desired fraction was lyophilized to yieldN-methyl-3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzamide(18.78 mg, 49.90 μmol, 20.1% yield, 100.0% purity) as white solid. ¹HNMR (500 MHz, CD₃OD) δ ppm 8.74-8.67 (m, 1H), 7.81 (dd, J=2.1, 8.9 Hz,1H), 7.59-7.51 (m, 3H), 7.42-7.35 (m, 1H), 7.39 (d, J=8.9 Hz, 1H),4.51-4.45 (m, 3H), 2.96-2.90 (m, 3H); ES-LCMS m/z 377.0 [M+H]⁺.

P-7

Step 1:N,N-Dimethyl-3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzamide

To a stirred solution of3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzoic acid(100 mg, 247.73 μmol, 1 eq) in DCM (10 mL) was added[chloro(dimethylamino)methylene]-dimethyl-ammonium; hexafluorophosphate(104.26 mg, 371.60 μmol, 1.5 eq), 1-methylimidazole (61.02 mg, 743.20μmol, 3 eq) and N-methylmethanamine; hydrochloride (30.30 mg, 371.60μmol, 1.5 eq). The reaction mixture was stirred at 29° C. for 6 h. Thereaction mixture was concentrated to yield a residue which was purifiedby preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobilephase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 43%-73%, 10 min).The desired fraction was lyophilized to yieldN,N-dimethyl-3-(2-methyltetrazol-5-yl)-4-[3-(trifluoromethyl)anilino]benzamide(21.49 mg, 55.05 μmol, 22.2% yield, 100.0% purity) as white solid. ¹HNMR (500 MHz, CD₃OD) δ ppm 8.31 (d, J=2.0 Hz, 1H), 7.57-7.52 (m, 3H),7.51-7.47 (m, 1H), 7.45-7.41 (m, 1H), 7.38-7.33 (m, 1H), 4.47 (s, 3H),3.13 (s, 6H); ES-LCMS m/z 391.0 [M+H]⁺.

I-41

Step 1: N-(3-Hydroxy-4-methyl-phenyl)prop-2-enamide

To a solution of 5-amino-2-methyl-phenol (1 g, 8.12 mmol, 1 eq) in THE(20 mL) was added DIEA (2.10 g, 16.24 mmol, 2.83 mL, 2.0 eq),prop-2-enoyl chloride (734.93 mg, 8.12 mmol, 662.10 μL, 1.0 eq). Themixture was stirred under N₂ at 0° C. for 1 hour. TLC (PE/EtOAc=1/1,R_(f)=0.52) showed the reaction was completed. Water (20 mL) was addedand the mixture extracted with EtOAc (30 mL×3). The combine organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated toyield N-(3-hydroxy-4-methyl-phenyl)prop-2-enamide (1.3 g, 6.53 mmol,80.4% yield, 89.0% purity) as a white solid which was used for the nextstep directly without further purification. ¹H NMR (500 MHz, CDCl₃) δppm 7.78 (s, 1H), 7.04 (d, J=7.9 Hz, 1H), 6.69-6.56 (m, 1H), 6.46 (d,J=16.9 Hz, 1H), 6.28-6.17 (m, 2H), 5.81 (d, J=10.4 Hz, 1H), 2.22 (s,3H); ES-LCMS m/z 178.0 [M+H]⁺.

Step 2:N-[3-[2-Bromo-5-(trifluoromethyl)phenoxy]-4-methyl-phenyl]prop-2-enamide

A mixture of N-(3-hydroxy-4-methyl-phenyl)prop-2-enamide (200 mg, 1.00mmol, 1 eq), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (387.74 mg, 1.10mmol, 1.1 eq), CuI (9.57 mg, 50.23 μmol, 0.05 eq), K₃PO₄ (426.45 mg,2.01 mmol, 2.0 eq) and 2-Picolinic acid (12.37 mg, 100.45 μmol, 0.1 eq)in DMSO (3 mL) was degassed and purged with N₂ for three times and themixture was stirred at 120° C. for 16 h under N₂ atmosphere. The mixturewas concentrated and water (80 mL) was added. The mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by preparative TLC (PE/EtOAc=5/1, R_(f)=0.14), and HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.05% HCl)-ACN]; B %: 60%-80%, 10 min) to yieldN-[3-[2-bromo-5-(trifluoromethyl)phenoxy]-4-methyl-phenyl]prop-2-enamide(5.64 mg, 14.09 μmol, 1.4% yield, 100.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.75 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.21(dd, J=6.1, 15.5 Hz, 3H), 6.94 (s, 1H), 6.46-6.36 (m, 1H), 6.27-6.12 (m,1H), 5.77 (d, J=10.2 Hz, 1H), 2.20 (s, 3H). ES-LCMS m/z 399.9, 401.9[M+H]⁺.

I-92 & I-93

Step 1: 1-Methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene

To a solution of 2-methyl-5-vinyl-phenol (9 g, 57.02 mmol, 1 eq) and1-iodo-3-(trifluoromethyl)benzene (13.96 g, 51.31 mmol, 7.38 mL, 0.9 eq)in DMSO (180 mL) was added pyridine-2-carboxylic acid (561.53 mg, 4.56mmol, 0.08 eq), K₃PO₄ (20.57 g, 96.93 mmol, 1.7 eq) and CuI (510.35 mg,2.68 mmol, 0.047 eq). The mixture was stirred at 120° C. for 12 h underN₂ atmosphere. The reaction mixture was added H₂O (150 mL) and extractedwith EtOAc (150 mL×3). The combined organic layers were washed with sat.aq. NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=200/1 to 10/1, TLC: PE/EtOAc=10/1,R_(f)=0.60) to yield1-methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene (7 g, 21.38mmol, 37.5% yield, 85.0% purity) as yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.42-7.36 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25-7.21 (m,1H), 7.18 (dd, J=2.0, 10.2 Hz, 2H), 7.06-6.98 (m, 2H), 6.64 (dd, J=11.0,17.6 Hz, 1H), 5.67 (d, J=17.2 Hz, 1H), 5.22 (d, J=11.0 Hz, 1H), 2.19 (s,3H); ES-LCMS no desired m z was detected.

Step 2:3-Bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

To a stirred solution of1-methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene (1 g, 3.05 mmol,1 eq) and dibromomethanone oxime (929.36 mg, 4.58 mmol, 1.5 eq) in EtOAc(15 mL) was added NaHCO₃ (2.57 g, 30.55 mmol, 10 eq). The reactionmixture was stirred at 25° C. for 12 h. The reaction mixture was dilutedwith H₂O (20 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=10:1, R_(f)=0.44) to yield3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(870 mg, 2.15 mmol, 70.5% yield, 99.0% purity) as light yellow liquid.¹H NMR (500 MHz, CDCl₃) δ ppm 7.43-7.39 (m, 1H), 7.31 (d, J=7.9 Hz, 2H),7.15-7.09 (m, 2H), 7.02 (dd, J=2.3, 8.2 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H),5.61 (dd, J=9.2, 10.8 Hz, 1H), 3.58 (dd, J=11.0, 17.2 Hz, 1H), 3.17 (dd,J=9.0, 17.2 Hz, 1H), 2.22 (s, 3H); ES-LCMS m/z 399.9, 401.9 [M+H]⁺.

Step 3:(5R)-5-[4-Mthyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(3-pyridyloxy)-4,5-dihydroisoxazole&(5S)-5-[4-Mthyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(3-pyridyloxy)-4,5-dihydroisoxazole

To a stirred solution of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(500 mg, 1.24 mmol, 0.9 eq) and pyridin-3-ol (130.70 mg, 1.37 mmol, 1eq) in DMSO (8 mL) was added K₃PO₄ (495.95 mg, 2.34 mmol, 1.7 eq),2-Picolinic acid (13.54 mg, 109.95 μmol, 0.08 eq) and CuI (13.09 mg,68.72 μmol, 0.05 eq). The reaction mixture was stirred at 120° C. for 12h under N₂ atmosphere. The reaction mixture was diluted with H₂O (10 mL)and extracted with EtOAc (25 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=2/1, R_(f)=0.45) to yield crude product which was separated bychiral SFC (column: DAICEL CHIRALPAK AD (column: DAICEL CHIRALPAK AD-H(250 mm*30 mm, 5 μm); mobile phase: [0.1% NHl₃.H₂O ETOH]; B %: 30%-30%,min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(40 mL) and lyophilized to yield(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(3-pyridyloxy)-4,5-dihydroisoxazole(40.02 mg, 96.58 μmol, 7.0% yield, 100% purity, SFC: R_(t)=1.090 min,ee=100%, [α]³⁰-1_(D)=+20.408 (MeOH, c=0.049 g/100 mL)) as red oil. ¹HNMR (500 MHz, CD₃OD) δ ppm 8.55 (d, J=2.7 Hz, 1H), 8.42 (dd, J=1.1, 4.8Hz, 1H), 7.88-7.81 (m, 1H), 7.54-7.46 (m, 2H), 7.41-7.33 (m, 2H), 7.25(dd, J=1.4, 7.9 Hz, 1H), 7.16-7.09 (m, 2H), 7.06 (d, J=1.4 Hz, 1H), 5.72(t, J=9.7 Hz, 1H), 3.66 (dd, J=10.2, 16.8 Hz, 1H), 3.25 (dd, J=9.2, 16.7Hz, 1H), 2.21 (s, 3H); ES-LCMS m/z 415.0 [M+H]⁺. Peak 2 was concentratedunder reduced pressure to yield a residue which was dissolved in MeCN(20 mL) and H₂O (40 mL) and lyophilized to yield(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(3-pyridyloxy)-4,5-dihydroisoxazole(15.24 mg, 36.78 μmol, 2.7% yield, 100% purity, SFC: R_(t)=1.249 min,ee=99.66%, [α]³⁰-1_(D)=−16.667 (MeOH, c=0.048 g/100 mL)) as red oil. ¹HNMR (500 MHz, CD₃OD) δ ppm 8.55 (d, J=2.7 Hz, 1H), 8.42 (dd, J=1.1, 4.7Hz, 1H), 7.84 (dd, J=1.5, 8.4 Hz, 1H), 7.54-7.46 (m, 2H), 7.41-7.33 (m,2H), 7.25 (dd, J=1.4, 7.9 Hz, 1H), 7.15-7.09 (m, 2H), 7.06 (d, J=1.5 Hz,1H), 5.72 (t, J=9.7 Hz, 1H), 3.66 (dd, J=10.2, 16.8 Hz, 1H), 3.25 (dd,J=9.2, 16.8 Hz, 1H), 2.21 (s, 3H); ES-LCMS m/z 415.0 [M+H]⁺.

I-52

Step 1: 4-(Trifluoromethyl)benzoic Acid

To a stirred solution of methyl 4-(trifluoromethyl)benzoate (2 g, 9.80mmol, 1.57 mL, 1 eq) in EtOH (10 mL) and H₂O (10 mL) was added LiOH H₂O(2.47 g, 58.80 mmol, 6 eq). The reaction mixture was stirred at 25° C.for 12 h. TLC (PE/EtOAc=5/1, R_(f)=0.05) indicated Reactant 1 wasconsumed completely and one new spot formed. The reaction mixture wasconcentrated under reduced pressure to remove EtOH. The residue wasadjust pH to 5 with 1 N HCl, filtered and concentrated the filter cakeunder reduced pressure to yield a residue which was used in the nextstep without further purification to yield 4-(trifluoromethyl)benzoicacid (1.86 g, 9.29 mmol, 94.8% yield, 95.0% purity) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.13 (d, J=8.1 Hz, 2H), 7.87 (d, J=7.6 Hz,2H); ES-LCMS no desired m z was detected.

Step 2: N-[l-[4-(Trifluoromethyl)benzoyl]-4-piperidyl]prop-2-enamide

To a stirred solution of 4-(trifluoromethyl)benzoic acid (200 mg, 999.37μmol, 1 eq), DIEA (387.48 mg, 3.00 mmol, 522.21 μL, 3 eq) and HATU(683.99 mg, 1.80 mmol, 1.8 eq) in DMF (5 mL) was addedN-(4-piperidyl)prop-2-enamide (194.67 mg, 1.20 mmol, 1.2 eq). Thereaction mixture was stirred at 25° C. for 3 h. The reaction mixture wasdiluted with H₂O (5 mL) and extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (15 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to yiled a residuewhich was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 μm; mobile phase: [water (0.04% NH₃.H₂O+10 mM NH₄HCO₃)-ACN];B %: 27%-57%, 10 min) to yieldN-[1-[4-(trifluoromethyl)benzoyl]-4-piperidyl]prop-2-enamide (96.69 mg,296.31 μmol, 29.7% yield, 100% purity) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.10 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.59(d, J=8.1 Hz, 2H), 6.25-6.16 (m, 1H), 6.13-6.04 (m, 1H), 5.58 (dd,J=2.2, 10.0 Hz, 1H), 4.33 (d, J=11.2 Hz, 1H), 3.99-3.82 (m, 1H), 3.45(d, J=11.5 Hz, 1H), 3.22-2.97 (m, 2H), 1.95-1.68 (m, 2H), 1.52-1.19 (m,2H); ES-LCMS m/z 327.0 [M+H]⁺.

I-53

Step 1: tert-Butyl N-(1-prop-2-enoyl-4-piperidyl)

A mixture of tert-butyl N-(4-piperidyl)carbamate (3 g, 14.98 mmol, 1 eq)and DIEA (5.79 g, 44.78 mmol, 7.8 mL, 2.99 eq) in DCM (10 mL) wasstirred at 28° C. The mixture was cooled to 0° C. and then prop-2-enoylchloride (1.67 g, 18.40 mmol, 1.5 mL, 1.23 eq) was added dropwise at 0°C. The resulting mixture was stirred at 28° C. for 6 h. TLC(PE/EtOAc=1/1, R_(f)=0.50) indicated Reactant 1 was consumed completelyand one new spot formed. The mixture was diluted with water (20 mL) andextracted with EtOAc (25 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1, R_(f)=0.50) to yieldtert-butyl N-(1-prop-2-enoyl-4-piperidyl)carbamate (1.5 g, 5.31 mmol,35.4% yield, 90.0% purity) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 6.90-6.68 (m, 2H), 6.04 (dd, J=2.4, 16.6 Hz, 1H), 5.62(dd, J=2.3, 10.4 Hz, 1H), 4.22 (d, J=12.7 Hz, 1H), 4.01-3.85 (m, 1H),3.50-3.40 (m, 1H), 3.12-3.00 (m, 1H), 2.80-2.66 (m, 1H), 1.76-1.66 (m,2H), 1.35 (s, 9H), 1.19 (t, J=11.1 Hz, 2H); ES-LCMS m/z 198.9[M-t-Bu+H]⁺.

Step 2: 1-(4-Amino-1-piperidyl)prop-2-en-1-one

A solution of tert-butyl N-(1-prop-2-enoyl-4-piperidyl)carbamate (1.5 g,5.31 mmol, 1 eq) in HCl/MeOH (20 mL) was stirred at 28° C. for 1 h. TLC(PE/EtOAc=1/1) indicated Reactant 1 was consumed completely. Thereaction mixture was concentrated under reduced pressure to yield1-(4-amino-1-piperidyl)prop-2-en-1-one (1.4 g, 3.67 mmol, 69.2% yield,50.0% purity, HCl) as light yellow oil, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.25 (brs, 2H), 6.78 (dd, J=10.4, 16.8 Hz, 1H), 6.06 (dd, J=2.3, 16.8 Hz, 1H),5.65 (dd, J=2.4, 10.5 Hz, 1H), 4.40-4.30 (m, 1H), 4.05 (d, J=13.7 Hz,1H), 3.22 (dd, J=5.1, 10.3 Hz, 1H), 3.11-3.01 (m, 1H), 2.73-2.62 (m,1H), 1.92 (d, J=7.3 Hz, 2H), 1.44-1.33 (m, 2H).

Step 3:1-[4-[[4-(Trifluoromethyl)phenyl]methylamino]-1-piperidyl]prop-2-en-1-one

To a solution of 1-(4-amino-1-piperidyl)prop-2-en-1-one (100 mg, 324.24μmol, 1 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (93.00 mg,389.07 μmol, 60.00 μL, 1.2 eq) in DCM (5 mL) was added DIEA (207.76 mg,1.61 mmol, 280.00 μL, 4.96 eq). The mixture was stirred at 28° C. for 12h. The reaction mixture was filtered and concentrated under reducedpressure to yield a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water (0.04%NH₃.H₂O+10 mM NH₄HCO₃)-ACN]; B %: 32%-62%, 10 min) to yield1-[4-[[4-(trifluoromethyl)phenyl]methylamino]-1-piperidyl]prop-2-en-1-one(29.78 mg, 95.35 μmol, 29.4% yield, 100.0% purity) as a colorless oil.¹H NMR (400 MHz, CD₃OD) δ ppm 7.64-7.58 (m, 2H), 7.56-7.51 (m, 2H), 6.74(dd, J=10.8, 16.9 Hz, 1H), 6.15 (dd, J=1.8, 16.8 Hz, 1H), 5.70 (dd,J=2.0, 10.5 Hz, 1H), 4.47 (d, J=13.2 Hz, 1H), 4.07 (d, J=13.2 Hz, 1H),3.87 (s, 2H), 3.13 (t, J=12.1 Hz, 1H), 2.86-2.71 (m, 2H), 1.99 (d,J=11.7 Hz, 2H), 1.38-1.24 (m, 2H); ES-LCMS m/z 313.0 [M+H]⁺.

I-54

Step 1: tert-Butyl 4-(prop-2-enoylamino)piperidine-1-carboxylate

To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (5 g, 24.97mmol, 1 eq) in DCM (60 mL) was added DIEA (4.84 g, 37.45 mmol, 6.52 mL,1.5 eq) at 0° C. then added prop-2-enoyl chloride (2.71 g, 29.96 mmol,2.44 mL, 1.2 eq). The mixture was stirred at 0-30° C. for 1 h under N₂atmosphere. The reaction mixture was diluted with water (50 mL) thenextracted with EtOAc (30 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=1/1, R_(f)=0.75) to yieldtert-butyl 4-(prop-2-enoylamino)piperidine-1-carboxylate (5.3 g, 20.84mmol, 83.5% yield, 100.0% purity) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.04 (d, J=7.6 Hz, 1H), 6.24-6.14 (m, 1H), 6.12-6.03 (m,1H), 5.57 (dd, J=2.3, 9.9 Hz, 1H), 3.95-3.69 (m, 3H), 2.85 (s, 2H), 1.73(dd, J=2.8, 12.6 Hz, 2H), 1.39 (s, 9H), 1.32-1.14 (m, 2H); ES-LCMS m/z255.1 [M+H]⁺, 199.0 [M-t-Bu+H]⁺.

Step 2: N-(4-Piperidyl)prop-2-enamide

To a solution of tert-butyl4-(prop-2-enoylamino)piperidine-1-carboxylate (1.3 g, 5.11 mmol, 1 eq)in MeOH (10 mL) and HCl/EtOAc (4 M, 1.28 mL, 1 eq). The mixture wasstirred at 25° C. for 1 h under N₂ atmosphere. The reaction mixture wasconcentrated to yield N-(4-piperidyl)prop-2-enamide (970 mg, 4.83 mmol,94.6% yield, 95% purity, HCl) as yellow oil which was used in the nextstep without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.15(s, 2H), 6.33-6.21 (m, 1H), 6.14-6.03 (m, 1H), 5.57 (dd, J=2.1, 10.1 Hz,1H), 3.94-3.83 (m, 1H), 3.23 (d, J=12.7 Hz, 2H), 2.98-2.89 (m, 2H), 1.90(dd, J=3.1, 13.6 Hz, 2H), 1.66 (q, J=10.3 Hz, 2H).

Step 3: N-(1-Benzyl-4-piperidyl)prop-2-enamide

To a solution of N-(4-piperidyl)prop-2-enamide (250 mg, 1.54 mmol, 1 eq)and bromomethylbenzene (263.41 mg, 1.54 mmol, 182.93 μL, 1 eq) in DCM(10 mL) was added DIEA (398.10 mg, 3.08 mmol, 536.52 μL, 2 eq). Themixture was stirred at 30° C. for 30 min under N₂ atmosphere. Thereaction mixture was concentrated to yield a residue which was purifiedby preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 20%-50%, 10 min). The desiredfraction was lyophilized to yield N-(1-benzyl-4-piperidyl)prop-2-enamide(110 mg, 449.31 μmol, 29.2% yield, 99.8% purity) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.99 (d, J=7.6 Hz, 1H), 7.36-7.20 (m, 5H),6.26-6.15 (m, 1H), 6.10-6.01 (m, 1H), 5.55 (dd, J=2.3, 10.1 Hz, 1H),3.65-3.55 (m, 1H), 3.44 (s, 2H), 2.74 (d, J=11.7 Hz, 2H), 2.00 (t,J=10.5 Hz, 2H), 1.73 (d, J=10.8 Hz, 2H), 1.46-1.34 (m, 2H); ES-LCMS m/z245.0 [M+H]⁺.

I-94 & I-95

Step 1: 1-(Trifluoromethyl)-3-(3-vinylphenoxy)benzene

To a stirred solution of 1-bromo-3-[3-(trifluoromethyl)phenoxy]benzene(1.1 g, 2.08 mmol, 1 eq) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (384.67 mg, 2.50 mmol,423.64 μL, 1.2 eq) in 1,4-dioxane (15 mL) and water (5 mL) was addedPd(dppf)Cl₂ (152.29 mg, 208.14 μmol, 0.1 eq) and Cs₂CO₃ (2.03 g, 6.24mmol, 3 eq). The reaction mixture bubbled with N₂ for 1 min then stirredat 100° C. for 30 min under microwave. TLC (PE/EtOAc=3:1, R_(f)=0.70)showed starting material was remained and one new spot was detected. Themixture was filtered through a celite pad, and the filtrate wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.65) to yield 1-(trifluoromethyl)-3-(3-vinylphenoxy)benzene (461mg, 1.66 mmol, 79.6% yield, 95.0% purity) as yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.69-7.54 (m, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.43-7.39(m, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.24 (s, 1H), 6.99 (dd,J=1.5, 7.8 Hz, 1H), 6.74 (dd, J=10.9, 17.7 Hz, 1H), 5.87 (d, J=17.6 Hz,1H), 5.30 (d, J=11.0 Hz, 1H).

Step 2:(5S)-3-Bromo-5-[3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole&(5R)-3-bromo-5-[3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

To a stirred solution of 1-(trifluoromethyl)-3-(3-vinylphenoxy)benzene(230 mg, 826.89 μmol, 1 eq) and dibromomethanone oxime (335.44 mg, 1.65mmol, 2 eq) in EtOAc (10 mL) was added NaHCO₃ (694.65 mg, 8.27 mmol, 10eq). The reaction mixture was stirred at 25° C. for 12 h. The mixturewas filtered through a celite pad and the filtrate was concentrated toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.60) to yield aresidue which was separated by SFC (column: REGIS (s, s) WHELK-O1 (250mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O IPA]; B %: 25%-25%, min) toyield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressureto yield a residue which was lyophilized to yield(5S)-3-bromo-5-[3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(31.26 mg, 80.95 μmol, 9.8% yield, 100% purity, SFC: R_(t)=2.074 min,ee=100%, [α]^(30.5) _(D)=−123.4, MeOH, c=0.047 g/100 mL) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.65-7.60 (m, 1H), 7.52-7.44 (m, 2H),7.33 (s, 1H), 7.32-7.28 (m, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.12 (s, 1H),7.07 (dd, J=1.7, 8.1 Hz, 1H), 5.73 (dd, J=9.2, 10.6 Hz, 1H), 3.77 (dd,J=10.8, 17.6 Hz, 1H), 3.37-3.33 (m, 1H); ES-LCMS m/z 385.9, 387.9[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield aresidue which was lyophilized to yield(5R)-3-bromo-5-[3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(44.06 mg, 110.67 μmol, 13.4% yield, 97% purity, SFC: R_(t)=2.525 min,ee=100%, [α]^(30.5) _(D)=+169.5, MeOH, c=0.039 g/100 mL) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.66-7.59 (m, 1H), 7.51 (d, J=8.1 Hz,1H), 7.47 (t, J=8.1 Hz, 1H), 7.35-7.28 (m, 2H), 7.22 (d, J=8.0 Hz, 1H),7.12 (s, 1H), 7.07 (dd, J=1.6, 8.2 Hz, 1H), 5.73 (dd, J=9.3, 10.5 Hz,1H), 3.77 (dd, J=10.9, 17.5 Hz, 1H), 3.38-3.33 (m, 1H); ES-LCMS m/z385.8, 387.8 [M+H]⁺.

I-96 & I-97

Step 1: 3-Methyl-2-[3-(trifluoromethyl)phenoxy]pyridine

A mixture of 3-(trifluoromethyl)phenol (2.0 g, 12.34 mmol, 1.48 mL, 1eq), 2-bromo-3-methyl-pyridine (1.70 g, 9.87 mmol, 1.10 mL, 0.8 eq), CuI(117.48 mg, 616.87 μmol, 0.05 eq), K₃PO₄ (5.24 g, 24.67 mmol, 2 eq) and2-Picolinic acid (151.89 mg, 1.23 mmol, 0.1 eq) in DMSO (40 mL) wasdegassed and purged with N₂ for three times and the mixture was stirredat 120° C. for 12 h under N₂ atmosphere. The mixture was added water (40mL), extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedto yield a residue which was purified by flash silica gel chromatography(From PE/EtOAc=1/0 to 5/1, R_(f)=0.52) to yield3-methyl-2-[3-(trifluoromethyl)phenoxy]pyridine (900 mg, 3.53 mmol,28.6% yield, 99.4% purity) as colorless liquid. ¹H NMR (400 MHz, CDCl₃)δ ppm 8.00 (dd, J=1.2, 5.1 Hz, 1H), 7.60-7.38 (m, 4H), 7.33 (d, J=8.2Hz, 1H), 6.97 (dd, J=4.9, 7.2 Hz, 1H), 2.37 (s, 3H); ES-LCMS m/z 254.0[M+H]⁺.

Step 2: 3-Methyl-1-oxido-2-[3-(trifluoromethyl)phenoxy]pyridine

To a solution of 3-methyl-2-[3-(trifluoromethyl)phenoxy]pyridine (900mg, 3.54 mmol, 1 eq) in DCM (30 mL) was added m-CPBA (3.60 g, 17.71mmol, 85% purity, 5 eq). The mixture was stirred at 25° C. for 12 h.sat.aq.Na₂S20₃ (30 mL) and aq. NaHCO₃ (4 M, 30 mL) were added. Themixture was extracted with DCM (50 mL×3). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to yield3-methyl-1-oxido-2-[3-(trifluoromethyl)phenoxy]pyridine (953 mg, 2.76mmol, 78.0% yield, 78.0% purity) as light yellow solid which was used innext step directly without further purification. ¹H NMR (400 MHz, CDCl₃)δ ppm 2.31-2.37 (m, 3H), 7.04 (d, J=8.22 Hz, 1H), 7.15-7.24 (m, 2H),7.36-7.41 (m, 3H), 8.36 (d, J=6.26 Hz, 1H); ES-LCMS m/z 270.0 [M+H]⁺.

Step 3: 6-Chloro-3-methyl-2-[3-(trifluoromethyl)phenoxy]pyridine

A mixture of3-methyl-1-oxido-2-[3-(trifluoromethyl)phenoxy]pyridin-1-ium (900 mg,2.61 mmol, 1 eq) and POCl₃ (32.68 g, 213.14 mmol, 19.81 mL, 81.74 eq)was stirred at 100° C. for 12 h under N₂. The reaction mixture wasconcentrated to give a residue which was cooled to 0° C., quenched bysat. aq NaHCO₃ (50 mL), extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue whichwas purified by flash silica gel chromatography (from PE/EtOAc=1/0 to10/1, TLC: PE/EtOAc=10/1, R_(f)=0.70) to yield6-chloro-3-methyl-2-[3-(trifluoromethyl)phenoxy]pyridine (700 mg, 1.50mmol, 57.6% yield, 61.8% purity) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.51 (s, 2H), 7.46 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H),7.01 (d, J=7.4 Hz, 1H), 2.33 (s, 3H); ES-LCMS m/z 287.9, 289.9 [M+H]⁺.

Step 4: 3-Methyl-2-[3-(trifluoromethyl)phenoxy]-6-vinyl-pyridine

To a solution of6-chloro-3-methyl-2-[3-(trifluoromethyl)phenoxy]pyridine (700 mg, 1.50mmol, 1 eq) in 1,4-dioxane (15 mL) were added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (347.42 mg, 2.26 mmol,382.62 μL, 1.5 eq), Cs₂CO₃ (979.96 mg, 3.01 mmol, 2 eq), Pd(dppf)Cl₂(110.04 mg, 150.38 μmol, 0.1 eq) and H₂O (5 mL). The mixture was stirredat 100° C. for 2 h under N₂. The mixture was concentrated and H₂O (40mL) was added. The mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashsilica gel chromatography (From PE/EtOAc=1/0 to 5/1, R_(f)=0.55) toyield 3-methyl-2-[3-(trifluoromethyl)phenoxy]-6-vinyl-pyridine (380 mg,1.02 mmol, 67.9% yield, 75% purity) as red liquid. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.44-7.36 (m, 5H), 6.93 (d, J=7.0 Hz, 1H), 6.59 (dd,J=10.6, 17.2 Hz, 1H), 5.95 (dd, J=1.6, 17.2 Hz, 1H), 5.29-5.26 (m, 1H),2.33 (s, 3H); ES-LCMS m/z 280.0 [M+H]⁺.

Step 5:(5R)-3-Bromo-5-[5-methyl-6-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole&(5S)-3-Bromo-5-[5-methyl-6-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole

To a solution of3-methyl-2-[3-(trifluoromethyl)phenoxy]-6-vinyl-pyridine (350.0 mg,940.0 0 μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (789.69 mg, 9.40mmol, 10.0 eq) and dibromomethanone oxime (381.3 mg, 1.89 mmol, 2.0 eq).The mixture was stirred at 25° C. for 12 h. TLC (PE/EtOAc=5:1,R_(f)=0.47) showed the reaction was completed. The mixture wasconcentrated and H₂O (30 mL) was added. The mixture was extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash silica gel chromatography (From PE/EtOAc=1/0 to 5/1,R_(f)=0.47) to yield the product which was separated by SFC (column:DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um); mobile phase: [0.1% NH₃H₂OETOH]; B %: 15%-15%, min) to yield(5R)-3-bromo-5-[5-methyl-6-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole(42.61 mg, 106.21 μmol, 11.3% yield, 100.0% purity, SFC: R_(t)=2.251min, ee=99.48%, [α]^(29.7) _(D)=+136 (MeOH, c=0.050 g/100 mL)) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59 (dd, J=0.8, 7.4 Hz, 1H),7.53-7.38 (m, 3H), 7.31 (d, J=7.8 Hz, 1H), 7.14 (d, J=7.4 Hz, 1H), 5.51(dd, J=6.8, 10.4 Hz, 1H), 3.47-3.30 (m, 2H), 2.36 (s, 3H); ES-LCMS m z400.9, 402.9 [M+H]⁺ and(5S)-3-bromo-5-[5-methyl-6-[3-(trifluoromethyl)phenoxy]-2-pyridyl]-4,5-dihydroisoxazole(45.53 mg, 113.5 μmol, 12.1% yield, 100.0% purity, SFC: R_(t)=1.853 min,ee=100%, [α]^(29.8) _(D)=−126 (MeOH, c=0.050 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59 (d, J=7.4 Hz, 1H), 7.54-7.38(m, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.14 (d, J=7.4 Hz, 1H), 5.51 (dd,J=7.0, 10.6 Hz, 1H), 3.47-3.30 (m, 2H), 2.36 (s, 3H); ES-LCMS m/z 400.9,402.9 [M+H]⁺.

I-98 & I-99

Step 1: 2-Methyl-5-vinyl-aniline

A mixture of 5-bromo-2-methyl-aniline (1.5 g, 8.06 mmol, 1 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.49 g, 9.67 mmol, 1.64mL, 1.2 eq) and Cs₂CO₃ (7.88 g, 24.19 mmol, 3 eq) in 1,4-dioxane (15 mL)and H₂O (5 mL) was added Pd(dppf)Cl₂ (589.93 mg, 806.24 μmol, 0.1 eq).The mixture was degassed and purged with N₂ for three times and stirredat 110° C. for 3 h under N₂ atmosphere. The mixture was concentrated andthen water (40 mL) was added. The mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with NaCl (50 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash silica gel chromatography (From PE/EtOAc=1/0 to 5/1, R_(f)=0.44)to yield 2-methyl-5-vinyl-aniline (604 mg, 4.17 mmol, 51.8% yield, 92%purity) as a red liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.07-6.98 (m,1H), 6.81-6.73 (m, 2H), 6.68-6.57 (m, 1H), 5.66 (dd, J=0.8, 17.6 Hz,1H), 5.16 (dd, J=0.8, 11.0 Hz, 1H), 3.60 (s, 2H), 2.20-2.15 (m, 3H);ES-LCMS m/z 134.0 [M+H]⁺.

Step 2: N-(2-Methyl-5-vinyl-phenyl)-5-(trifluoromethyl)pyridin-3-amine

A mixture of 2-methyl-5-vinyl-aniline (300.0 mg, 2.07 mmol, 1 eq),3-bromo-5-(trifluoromethyl)pyridine (468.31 mg, 2.07 mmol, 1 eq),t-BuONa (398.30 mg, 4.14 mmol, 2.0 eq), RuPhos (193.39 mg, 414.45 μmol,0.2 eq) and Pd₂(dba)₃ (189.76 mg, 207.22 μmol, 0.1 eq in toluene (20.0mL) was stirred at 100° C. for 12 h under N₂ atmosphere. The mixture wasconcentrated and then sat.aq.NaHCO₃ (80 mL) was added. The mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (FromPE/EtOAc=1/0 to 5/1, R_(f)=0.41) to yieldN-(2-methyl-5-vinyl-phenyl)-5-(trifluoromethyl)pyridin-3-amine (420 mg,1.39 mmol, 67.0% yield, 92% purity) as a red solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.42-8.31 (m, 2H), 7.22 (s, 2H), 7.19-7.15 (m, 1H), 6.65(dd, J=11.0, 17.6 Hz, 1H), 5.68 (d, J=17.6 Hz, 2H), 5.23 (d, J=11.0 Hz,1H), 2.27-2.20 (m, 3H); ES-LCMS m/z 279.0 [M+H]⁺.

Step 3:N-[5-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-phenyl]-5-(trifluoromethyl)pyridin-3-amine&N-[5-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-phenyl]-5-(trifluoromethyl)pyridin-3-amine

To a solution ofN-(2-methyl-5-vinyl-phenyl)-5-(trifluoromethyl)pyridin-3-amine (400.0mg, 1.32 mmol, 1.0 eq) in EtOAc (10.0 mL) was added NaHCO₃ (1.11 g,13.22 mmol, 10.0 eq) and dibromomethanone oxime (536.47 mg, 2.64 mmol,2.0 eq) under N₂. The mixture was stirred at 25° C. for 12 h. Themixture was concentrated and water (80 mL) was added. The mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash silica gel chromatography (FromPE/EtOAc=1/0 to 5/1, R_(f)=0.20) to yield the product which wasseparated by SFC (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um);mobile phase: [0.1% NH₃H₂O ETOH]; B %: 50%-50%, min) to yieldN-[5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-phenyl]-5-(trifluoromethyl)pyridin-3-amine(17.52 mg, 43.78 μmol, 3.3% yield, 100% purity, SFC: R_(t)=1.155 min,ee=99.66%, [α]^(29.8) _(D)=+153.333 (MeOH, c=0.030 g/100 mL)) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.38 (d, J=8.2 Hz, 2H), 7.30(d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.10-7.04 (m, 1H), 5.68-5.57 (m, 2H),3.61 (dd, J=10.8, 17.4 Hz, 1H), 3.18 (dd, J=9.0, 17.2 Hz, 1H), 2.26 (s,3H); ES-LCMS m/z 399.9, 401.9 [M+H]⁺ andN-[5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-phenyl]-5-(trifluoromethyl)pyridin-3-amine(35.84 mg, 89.11 μmol, 6.7% yield, 99.5% purity, SFC: R_(t)=0.666 min,ee=100%, [α]^(29.7) _(D)=−140 (MeOH, c=0.020 g/100 mL)) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ ppm 8.38 (d, J=9.0 Hz, 1H), 8.42-8.33 (m, 1H),7.30 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J=7.4 Hz, 1H), 5.68-5.56(m, 2H), 3.61 (dd, J=11.0, 17.2 Hz, 1H), 3.18 (dd, J=8.8, 17.4 Hz, 1H),2.26 (s, 3H); ES-LCMS m z 399.9, 401.9 [M+H]⁺.

I-42

Step 1: 7-[3-(Trifluoromethyl)phenoxy]quinolin-5-amine

To a mixture of 5-bromo-7-[3-(trifluoromethyl)phenoxy]quinoline (500 mg,1.22 mmol, 1 eq) and tert-butyl carbamate (715.96 mg, 6.11 mmol, 5 eq)in 1,4-dioxane (2 mL) was added Cs₂CO₃ (1.19 g, 3.67 mmol, 3 eq)Pd(OAc)₂ (27.44 mg, 122.23 μmol, 0.1 eq) and XPhos (58.27 mg, 122.23μmol, 0.1 eq) under N₂ atmosphere. The mixture was stirred under N₂atmosphere at 120° C. for 12 h. The mixture was filtered and thefiltrate was diluted with H₂O (50 mL) and extracted with EtOAc (40mL×3). The combine organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated to yield a residue which was purified by flashsilica gel chromatography (from pure PE to PE/EtOAc=9/1, TLC:PE/EtOAc=1/1, R_(f)=0.6) to yield7-[3-(trifluoromethyl)phenoxy]quinolin-5-amine (200 mg, 525.86 μmol,43.0% yield, 80.0% purity) as yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δppm 8.73 (dd, J=1.5, 4.1 Hz, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.68-7.64 (m,1H), 7.57-7.54 (m, 1H), 7.47-7.39 (m, 2H), 7.30 (dd, J=4.3, 8.4 Hz, 1H),6.62 (d, J=2.0 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.29 (s, 2H); ES-LCMSm/z 305.1 [M+H]⁺.

Step 2: N-[7-[3-(Trifluoromethyl)phenoxy]-5-quinolyl]prop-2-enamide

To a solution of 7-[3-(trifluoromethyl)phenoxy]quinolin-5-amine (200 mg,525.86 μmol, 1 eq) in DCM (5 mL) was added DIEA (135.93 mg, 1.05 mmol,183.19 μL, 2 eq) and prop-2-enoyl chloride (71.39 mg, 788.78 μmol, 64.32μL, 1.5 eq). The mixture was stirred at 25° C. for 12 h. The mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combineorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by preparative HPLC(column: YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 49%-69%, 10 min) andlyophilized to yieldN-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]prop-2-enamide (47.42 mg,132.34 μmol, 25.2% yield, 100.0% purity) as a yellow solid. ¹H NMR (500MHz, CD₃OD) δ ppm 8.82 (dd, J=2.0, 4.5 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H),7.83 (d, J=2.0 Hz, 1H), 7.69-7.63 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.52(dd, J=4.5, 9.0 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.29 (d,J=2.0 Hz, 1H), 6.65 (dd, J=10.5, 16.9 Hz, 1H), 6.46 (dd, J=1.5, 16.9 Hz,1H), 5.89 (dd, J=1.5, 10.5 Hz, 1H); ES-LCMS m/z 359.0 [M+H]⁺.

I-100 & I-101

Step 1: 7-[3-(Trifluoromethyl)phenoxy]-5-vinyl-quinoline

To a mixture of 5-bromo-7-[3-(trifluoromethyl)phenoxy]quinoline (320 mg,782.29 μmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(722.91 mg, 4.69 mmol, 796.15 μL, 6 eq) in 1,4-dioxane (8 mL) was addedCs₂CO₃ (2 M, 1.17 mL, 3 eq) and Pd(dppf)Cl₂ (57.24 mg, 78.23 μmol, 0.1eq) under N₂ atmosphere. The mixture was stirred at 80° C. in microwave(0 bar) for 1 h under N₂ atmosphere. TLC (PE/EtOAc=4/1, R_(f)=0.40)showed starting material was consumed and one major new spot wasdetected. The mixture was diluted with H₂O (5 mL) and extracted withEtOAc (10 mL×3). The combine organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby preparative TLC (PE/EtOAc=4/1, TLC: PE/EtOAc=4/1, R_(f)=0.40) toyield 7-[3-(trifluoromethyl)phenoxy]-5-vinyl-quinoline (150 mg, 428.18μmol, 54.7% yield, 90.0% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.89 (dd, J=1.5, 4.0 Hz, 1H), 8.66 (d, J=8.5 Hz, 1H),7.74-7.66 (m, 2H), 7.64-7.47 (m, 5H), 7.36 (d, J=2.5 Hz, 1H), 6.01 (d,J=17.5 Hz, 1H), 5.61 (d, J=11.0 Hz, 1H); ES-LCMS m/z 316.0 [M+H]⁺

Step 2:(5R)-3-Bromo-5-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]-4,5-dihydroisoxazole

To a solution of 7-[3-(trifluoromethyl)phenoxy]-5-vinyl-quinoline (150mg, 428.18 μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (359.71 mg,4.28 mmol, 10 eq) and dibromomethanone oxime (173.70 mg, 856.36 μmol, 2eq). The mixture was stirred at 30° C. for 12 h. TLC (PE/EtOAc=2/1,R_(f)=0.40) showed starting material was consumed completely and onemajor new spot was detected. The mixture was filtered and the filtratewas concentrated to yield a residue which was purified by preparativeTLC (PE/EtOAc=2/1, TLC: PE/EtOAc=2/1, R_(f)=0.40) and then bypreparative SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm);mobile phase: [0.1% NH₃H₂O EtOH]; B %: 40%-40%) to yield Peak 1 and Peak2. Peak 1 was concentrated under reduced pressure to yield a residuewhich was dissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized toyield(5R)-3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]-4,5-dihydroisoxazole(30.42 mg, 69.58 μmol, 16.3% yield, 100.0% purity, R_(t)=1.617, ee=100%,[α]30.4_(D)=+24.488 (MeOH, c=0.109 g/100 mL)) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.96-8.87 (m, 1H), 8.13 (d, J=8.5 Hz, 1H),7.58-7.52 (m, 2H), 7.51-7.46 (m, 1H), 7.46-7.37 (m, 3H), 7.32 (d, J=8.0Hz, 1H), 6.30 (dd, J=9.0, 11.1 Hz, 1H), 3.87 (dd, J=11.0, 17.0 Hz, 1H),3.28 (dd, J=8.5, 17.0 Hz, 1H); ES-LCMS m/z 436.9, 438.9. [M+H]⁺. Peak 2was concentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield(5S)-3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-5-quinolyl]-4,5-dihydroisoxazole(29.00 mg, 66.33 μmol, 15.49% yield, 100% purity, R_(t)=2.635,ee=99.86%, [α]30.4_(D)=−9.992 (MeOH, c=0.088 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.91 (dd, J=1.5, 4.2 Hz, 1H), 8.13(d, J=8.5 Hz, 1H), 7.59-7.51 (m, 2H), 7.50-7.47 (m, 1H), 7.44 (d, J=2.5Hz, 1H), 7.43-7.38 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 6.30 (dd, J=9.0,11.0 Hz, 1H), 3.87 (dd, J=11.0, 17.0 Hz, 1H), 3.28 (dd, J=8.5, 17.0 Hz,1H); ES-LCMS m z 436.9, 438.9, [M+H]⁺.

I-102 & I-104

Step 1: 1-Methyl-2-(3-(trifluoromethyl)phenoxy)-4-vinylbenzene

To a solution of 2-methyl-5-vinyl-phenol (981.31 mg, 6.87 mmol, 1.1 eq)in DMSO (30 mL) was added 1-iodo-3-(trifluoromethyl)benzene (1.7 g, 6.25mmol, 899.47 μL, 1 eq), CuI (59.51 mg, 312.49 μmol, 0.05 eq), K₃PO₄(2.65 g, 12.50 mmol, 2.0 eq) and 2-picolinic acid (76.94 mg, 624.99μmol, 0.1 eq). The mixture was stirred under N₂ atmosphere at 120° C.for 16 h. TLC (PE/EtOAc=100/1, R_(f)=0.6) showed the reaction wascompleted. The mixture was diluted with water (30 mL) and extracted withEtOAc (30 mL×3). The combine organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby flash silica gel chromatography (from pure PE to PE/EtOAc=100/1, TLC:PE/EtOAc=100/1, R_(f)=0.6) to yield1-methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene (1.3 g, 3.74mmol, 59.8% yield, 80.0% purity) as yellow oil. ¹H NMR (400 MHz, CD₃OD)δ ppm 7.52-7.50 (m, 1H), 7.30-7.26 (m, 3H), 7.14-7.10 (m, 3H), 6.68 (d,J=10.8, 17.6 Hz, 1H), 5.70 (d, J=17.4 Hz, 1H), 5.20 (d, J=11.0 Hz, 1H),2.17 (s, 3H).

Step 2:3-Bromo-5-(4-methyl-3-(3-(trifluoromethyl)phenoxy)phenyl)-4,5-dihydroisoxazole

To a solution of dibromomethanone oxime (1.02 g, 5.05 mmol, 1.2 eq) inEtOAc (20 mL) was added NaHCO₃ (3.53 g, 42.05 mmol, 10 eq) and1-methyl-2-[3-(trifluoromethyl)phenoxy]-4-vinyl-benzene (1.3 g, 4.20mmol, 1 eq). The mixture was stirred at 30° C. for 16 h. Afterfiltration, the filtrate was concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 5/1,TLC: PE/EtOAc=5/1, R_(f)=0.56) to yield3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(270 mg, 665.24 μmol, 15.8% yield, 98.6% purity) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.45-7.38 (m, 1H), 7.31 (d, J=7.8 Hz, 2H),7.15-7.10 (m, 2H), 7.02 (dd, J=2.3, 8.2 Hz, 1H), 6.92 (d, J=1.6 Hz, 1H),5.61 (dd, J=9.4, 10.6 Hz, 1H), 3.59 (dd, J=11.0, 17.2 Hz, 1H), 3.17 (dd,J=9.0, 17.2 Hz, 1H), 2.22 (s, 3H); ES-LCMS m/z 399.9, 401.9 [M+H]⁺.

Step 3:(S)-3-Chloro-5-(4-methyl-3-(3-(trifluoromethyl)phenoxy)phenyl)-4,5-dihydroisoxazoleand(R)—3-chloro-5-(4-methyl-3-(3-(trifluoromethyl)phenoxy)phenyl)-4,5-dihydroisoxazole

To a solution of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(150 mg, 369.58 μmol, 1 eq) in 1,4-dioxane (2 mL) was added hydrogenchloride (1.02 g, 27.98 mmol, 1 mL, 75.70 eq) (4 M in water). Themixture was stirred at 40° C. for 16 h. The reaction mixture was dilutedwith water (10 mL) and extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was separated by chiral SFC (column: REGIS (s,s) WHELK-O1 (250mm*30 mm, 5 um); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 20%-20%) toyield peak 1 and peak 2. Peak 1 was concentrated under reduced pressureto yield a residue which was dissolved in MeCN (100 mL) and H₂O (100 mL)and lyophilized to yield(5S)-3-chloro-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(14.22 mg, 38.43 μmol, 10.4% yield, 96.1% purity, SFC: R_(t)=1.71,ee=100%, [α]^(24.2) _(D)=−70 (MeOH, c=0.020 g/100 mL)) as yellow oil. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.55-7.49 (m, 1H), 7.41-7.33 (m, 2H), 7.19(dd, J=1.5, 7.8 Hz, 1H), 7.15-7.07 (m, 2H), 6.99 (d, J=1.2 Hz, 1H),5.77-5.70 (m, 1H), 3.65 (dd, J=10.8, 17.4 Hz, 1H), 3.18 (dd, J=9.3, 17.4Hz, 1H), 2.20 (s, 3H); ES-LCMS m/z 356.0, 358.0 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and H₂O (10 mL) and lyophilized to yield(5R)-3-chloro-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(21.42 mg, 60.21 μmol, 16.3% yield, 100.0% purity, SFC: R_(t)=2.876,ee=100.0%, [α]^(24.2) _(D)=+10 (MeOH, c=0.020 g/100 mL)) as yellow oil.¹H NMR (400 MHz, CD₃OD) δ ppm 7.52 (t, J=8.4 Hz, 1H), 7.41-7.34 (m, 2H),7.19 (d, J=6.3 Hz, 1H), 7.15-7.08 (m, 2H), 6.99 (s, 1H), 5.74 (t, J=10.2Hz, 1H), 3.65 (dd, J=10.8, 17.4 Hz, 1H), 3.24-3.13 (m, 1H), 2.20 (s,3H); ES-LCMS m/z 355.9, 357.9 [M+H]⁺.

I-105 & I-106

Step 1: 1-Bromo-2-fluoro-5-iodo-4-methyl-benzene

To a solution of 5-bromo-4-fluoro-2-methyl-aniline (3 g, 14.70 mmol, 1eq) in MeCN (30 mL) cooled to 0° C. was added H₂SO₄ (3.56 g, 36.32 mmol,1.94 mL, 2.47 eq) dissolved in H₂O (5 mL). After stirring for 5 min, asolution of NaNO₂ (2.03 g, 29.41 mmol, 2 eq) in H₂O (5 mL) was addeddropwise and the reaction mixture was stirred for an additional 15 minat 0° C. Then a solution of NaI (8.82 g, 58.81 mmol, 4 eq) in H₂O (5 mL)was added. The reaction was stirred for an additional 20 min at 25° C.To the mixture was added water (100 mL) and extracted with ethyl acetate(100 mL×3). The combined organic phase was washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=200/1 to 100/1, TLC: PE/EtOAc=100/1, R_(f)=0.52) to yield1-bromo-2-fluoro-5-iodo-4-methyl-benzene (4.6 g, 13.15 mmol, 89.4%yield, 90% purity) was obtained as red liquid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.10 (d, J=7.4 Hz, 1H), 7.42 (d, J=10.6 Hz, 1H), 2.33 (s, 3H).

Step 2: 1-Bromo-2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]benzene

To a solution of 1-bromo-2-fluoro-5-iodo-4-methyl-benzene (1.5 g, 4.29mmol, 1 eq) and 3-(trifluoromethyl)phenol (590.69 mg, 3.64 mmol, 437.55μL, 0.85 eq) in DMSO (15 mL) was added CuI (40.82 mg, 214.34 μmol, 0.05eq), pyridine-2-carboxylic acid (42.22 mg, 342.94 μmol, 0.08 eq) andK₃PO₄ (1.52 g, 7.16 mmol, 1.67 eq). The mixture was stirred at 120° C.for 12 h. To the mixture was added water (50 mL) and extracted withethyl acetate (50 mL×3). The combined organic phase was washed withbrine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=200/1 to 10/1, TLC: PE/EtOAc=10/1,R_(f)=0.40) to yield1-bromo-2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]benzene (1 g,2.01 mmol, 46.8% yield, 70% purity) as red oil. ¹H NMR (400 MHz, CD₃OD)δ ppm 7.54-7.51 (m, 1H), 7.39 (d, J=4.6 Hz, 1H), 7.21 (d, J=5.4 Hz, 1H),7.18-7.14 (m, 2H), 7.10 (d, J=6.1 Hz, 1H), 2.19-2.14 (m, 3H).

Step 3: 1-Fluoro-5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-vinyl-benzene

To a solution of1-bromo-2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]benzene (1 g,2.01 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(463.21 mg, 3.01 mmol, 510.14 μL, 1.5 eq) in 1,4-dioxane (10 mL) and H₂O(2 mL) was added Pd(dppf)Cl₂ (146.71 mg, 200.51 μmol, 0.1 eq) and Cs₂CO₃(1.96 g, 6.02 mmol, 3 eq). The mixture was stirred at 100° C. for 2 hunder N₂ atmosphere. To the mixture was added water (30 mL) andextracted with ethyl acetate (30 mL×3). The combined organic phase waswashed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=200/1 to 10/1, TLC:PE/EtOAc=10/1, R_(f)=0.39) to yield1-fluoro-5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-vinyl-benzene (350mg, 945.12 μmol, 47.1% yield, 80% purity) colorless oil. ¹H NMR (500MHz, CD₃OD) δ ppm 7.50 (t, J=7.9 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.18(d, J=6.6 Hz, 1H), 7.11 (s, 1H), 7.08 (dd, J=4.8, 9.2 Hz, 2H), 6.84-6.78(m, 1H), 5.76 (d, J=17.9 Hz, 1H), 5.36-5.32 (m, 1H), 2.15 (s, 3H).

Step 4:(5S)-3-Bromo-5-[2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(5R)-3-Bromo-5-[2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

To a solution of1-fluoro-5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-vinyl-benzene (350mg, 945.12 μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (793.99 mg,9.45 mmol, 367.59 μL, 10 eq) and dibromomethanone oxime (287.55 mg, 1.42mmol, 1.5 eq). The mixture was stirred at 25° C. for 12 h. To themixture was added water (30 mL) and extracted with ethyl acetate (30mL×3). The combined organic phase was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=200/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.38) to yield aproduct. The product was separated by SFC (column: REGIS (s,s) WHELK-O1(250 mm*30 mm, 5 μm); mobile phase: [0.1% NH3-H₂O IPA]; B %: 20%-20%,min) to yield peak 1 (R_(t)=1.679 min, ee=100%) and peak 2 (R_(t)=2.064min, ee=100%). Peak 1 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (20 mL) and H₂O (40 mL) andlyophilized to yield(5S)-3-bromo-5-[2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(77.64 mg, 185.66 μmol, 19.6% yield, 100% purity, SFC: R_(t)=1.679,ee=100%, [α]^(28.3) _(D)=−198.068 (MeOH, c=0.0414 g/100 mL)) ascolorless oil. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.54-7.48 (m, 1H), 7.36 (d,J=7.8 Hz, 1H), 7.17 (d, J=10.8 Hz, 1H), 7.12 (s, 1H), 7.08 (dd, J=2.2,8.3 Hz, 1H), 7.02 (d, J=6.6 Hz, 1H), 5.82 (dd, J=8.5, 11.1 Hz, 1H), 3.75(dd, J=11.2, 17.5 Hz, 1H), 3.30-3.22 (m, 1H), 2.19 (s, 3H); ES-LCMS m/z418.1, 420.1 [M+H]⁺. Peak 2 was concentrated under reduced pressure toyield a residue which was dissolved in MeCN (20 mL) and H₂O (40 mL) andlyophilized to yield(5R)-3-bromo-5-[2-fluoro-4-methyl-5-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(74.74 mg, 176.76 μmol, 18.7% yield, 98.9% purity, SFC: R_(t)=2.064,ee=100%, [α]^(28.3) _(D)=+185.941 (MeOH, c=0.0441 g/100 mL)) ascolorless oil. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.51 (t, J=8.0 Hz, 1H),7.36 (d, J=7.8 Hz, 1H), 7.17 (d, J=10.8 Hz, 1H), 7.13 (s, 1H), 7.08 (dd,J=2.2, 8.3 Hz, 1H), 7.02 (d, J=6.4 Hz, 1H), 5.82 (dd, J=8.4, 11.1 Hz,1H), 3.75 (dd, J=11.1, 17.4 Hz, 1H), 3.29-3.23 (m, 1H), 2.19 (s, 3H);ES-LCMS m/z 418.1, 420.1 [M+H]⁺.

I-107 & I-108

Step 1:3-Imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

A mixture of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(300 mg, 584.72 μmol, 1 eq), imidazole (199.03 mg, 2.92 mmol, 26.48 μL,5 eq) and Cs₂CO₃ (571.54 mg, 1.75 mmol, 3 eq) in MeCN (12 mL) wasstirred at 80° C. for 3 h. TLC (PE/EtOAc=1/1, R_(f)=0.28) indicated thestarting material was consumed, and one major new spot was detected. Thereaction mixture was quenched by addition of water (50 mL), thenextracted with EtOAc (50 mL×3). The organic layer was washed with brine(20 mL), dried over Na₂SO₄, filtered, then concentrated. The residue waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 1/1,TLC: PE/EtOAc=1/1, R_(f)=0.28) to yield a3-imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(150 mg, 386.47 μmol, 66.0% yield, 99.8% purity) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.82 (s, 1H), 7.42-7.40 (m, 2H), 7.35-7.33 (m,2H), 7.32-7.31 (m, 3H), 7.19-7.14 (m, 1H), 6.99 (d, J=1.2 Hz, 1H),5.82-5.77 (m, 1H), 3.85-3.79 (m, 1H), 3.43-3.37 (m, 1H), 2.23 (s, 3H);ES-LCMS m/z 388.2 [M+H]⁺.

Step 2:(5S)-3-Imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole&(5R)-3-Imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

3-Imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(150 mg, 386.47 μmol, 1 eq) was separated by SFC (column: DAICELCHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B%: 25%-25%, min) to yield peak 1 (3.357) and peak 2 (3.507). Peak 2 waswas further separated by SFC (column: DAICEL CHIRALCEL OD-H (250 mm*30mm, 5 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B %: 30%-30%, min) to yieldpeak 2 (3.507). Peak 1 was concentrated under reduced pressure to yielda residue which was dissolved in MeCN (20 mL) and H₂O (10 mL) andlyophilized to yield(5S)-3-imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(22.94 mg, 59.22 μmol, 15.3% yield, 100% purity) (SFC: R_(t)=3.348,ee=99.78%, [α]^(27.3) _(D)=−254.901 (MeOH, c=0.051 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CD₃OD) δ ppm 8.10 (s, 1H), 7.59 (s, 1H), 7.50(t, J=8.0 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.27(dd, J=1.4, 7.9 Hz, 1H), 7.15-7.05 (m, 4H), 5.83 (t, J=10.0 Hz, 1H),3.97 (dd, J=10.7, 16.8 Hz, 1H), 3.55 (dd, J=9.2, 16.9 Hz, 1H), 2.21 (s,3H); ES-LCMS m z 281.1 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(10 mL) and lyophilized to yield(5R)-3-imidazol-1-yl-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(24.17 mg, 61.40 μmol, 15.8% yield, 98.4% purity) (SFC: R_(t)=3.507,ee=94.76%, [α]^(27.1) _(D)=+164.417 (MeOH, c=0.1002 g/100 mL)) as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.10 (s, 1H), 7.59 (t, J 1.4Hz, 1H), 7.54-7.47 (m, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.8 Hz,1H), 7.27 (dd, J 1.7, 7.8 Hz, 1H), 7.16-7.06 (m, 4H), 5.83 (t, J=9.9 Hz,1H), 3.97 (dd, J=10.7, 16.9 Hz, 1H), 3.55 (dd, J=9.3, 16.9 Hz, 1H), 2.21(s, 3H); ES-LCMS m/z 281.1 [M+H]⁺.

I-109 & I-110

Step 1: 5-Bromo-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline

A mixture of 5-bromo-2-methoxy-aniline (500 mg, 2.47 mmol, 1 eq),[3-(trifluoromethyl)phenyl]boronic acid (470.00 mg, 2.47 mmol, 1 eq),DIEA (639.65 mg, 4.95 mmol, 862.06 μL, 2 eq) and Cu(OAc)₂ (539.38 mg,2.97 mmol, 1.2 eq) in DCM (10 mL) was stirred at 25° C. for 12 h underN₂. The reaction mixture was quenched by addition of water (100 mL),then extracted with DCM (100 mL×3). The organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered, concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=1/0 to 10/1, TLC: PE/EtOAc=10/1, R_(f)=0.26) to yield5-bromo-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline (650 mg, 1.82mmol, 73.6% yield, 97.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃)δ ppm 7.43-7.41 (m, 1H), 7.36-7.32 (m, 3H), 7.25-7.21 (m, 1H), 7.00 (dd,J=2.0, 8.4 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 3.88 (s, 3H);ES-LCMS m/z 345.9, 347.9 [M+H]⁺.

Step 2: 2-Methoxy-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline

A mixture of 5-bromo-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline (600mg, 1.68 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(388.12 mg, 2.52 mmol, 427.44 μL, 1.5 eq), and Cs₂CO₃ (1.10 g, 3.36mmol, 2 eq) in 1,4-dioxane (12 mL) and H₂O (3 mL) was degassed with N₂—,Pd(dppf)Cl₂ (61.51 mg, 84.00 μmol, 0.05 eq) was added and then heated to100° C. for 2 h under N₂. The reaction mixture was quenched by additionof water (50 mL), extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 10/1,TLC: PE/EtOAc=10/1, R_(f)=0.36) to yield2-methoxy-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline (270 mg, 828.55μmol, 49.3% yield, 90.0% purity) as yellow oil. ¹H NMR (500 MHz, CDCl₃)δ ppm 7.43-7.34 (m, 3H), 7.31 (d, J=8.1 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H),6.98 (dd, J=2.1, 8.3 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.64 (dd, J=10.9,17.5 Hz, 1H), 6.21 (br s, 1H), 5.58 (dd, J=0.6, 17.5 Hz, 1H), 5.14 (dd,J 0.6, 10.8 Hz, 1H), 3.90 (s, 3H); ES-LCMS m/z 294.0 [M+H]⁺.

Step 3:5-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline&5-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of 2-methoxy-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline(270 mg, 828.55 μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (696.07mg, 8.29 mmol, 10 eq) and dibromomethanone oxime (252.09 mg, 1.24 mmol,1.5 eq). The mixture was stirred at 30° C. for 12 h. The reactionmixture was quenched by addition of water (50 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.44) to yieldproduct. The product was separated by SFC (column: DAICEL CHIRALPAK AD-H(250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B %: 40%-40%,min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(10 mL) and lyophilized to yield5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline(66.73 mg, 154.77 μmol, 18.6% yield, 96.3% purity) (SFC: R_(t)=1.178,ee=100%, [α]^(28.3) _(D)=+191.78 (MeOH, c=0.073 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.42-7.37 (m, 1H), 7.35-7.29 (m,2H), 7.26 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.93-6.90 (m, 2H), 6.28 (s,1H), 5.59 (dd, J=9.3, 10.7 Hz, 1H), 3.98-3.86 (m, 3H), 3.57 (dd, J=10.8,17.2 Hz, 1H), 3.20 (dd, J=9.2, 17.3 Hz, 1H); ES-LCMS m/z 415.1, 417.1[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (20 mL) and H₂O (10 mL) andlyophilized to yield5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methoxy-N-[3-(trifluoromethyl)phenyl]aniline(66.73 mg, 154.77 μmol, 18.6% yield, 96.3% purity) (SFC: R_(t)=1.712,ee=99.88%, [α]^(28.3) _(D)=−209.52 (MeOH, c=0.063 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.42-7.37 (m, 1H), 7.34-7.29 (m,2H), 7.26 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.91 (s, 2H), 6.28 (s, 1H),5.59 (dd, J=9.3, 10.7 Hz, 1H), 3.91 (s, 3H), 3.57 (dd, J=10.8, 17.3 Hz,1H), 3.20 (dd, J=9.2, 17.3 Hz, 1H); ES-LCMS m/z 415.1, 417.1 [M+H]⁺.

I-145 & I-146

Step 1: tert-Butyl (3R)-3-formylpiperidine-1-carboxylate

To a solution of tert-butyl(3R)-3-(hydroxymethyl)piperidine-1-carboxylate (4 g, 18.58 mmol, 1 eq)in DCM (40 mL) was added Dess-Martin (11.03 g, 26.01 mmol, 8.05 mL, 1.4eq). The mixture was stirred at 25° C. for 2 h. The reaction mixture wasfiltered through a pad of celite and the filtrate was concentrated toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=3/1, R_(f)=0.45) to yieldtert-butyl (3R)-3-formylpiperidine-1-carboxylate (2.8 g, 9.72 mmol,52.3% yield, 74.0% purity) as a colorless oil. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 9.62-9.55 (m, 1H), 3.82-3.61 (m, 1H), 3.42 (s, 2H), 3.07 (t, J=9.5Hz, 1H), 2.45 (tt, J=4.2, 8.1 Hz, 1H), 1.89-1.81 (m, 1H), 1.65-1.57 (m,1H), 1.56-1.50 (m, 1H), 1.38 (s, 9H), 1.36 (br s, 1H).

Step 2: tert-Butyl (3S)-3-vinylpiperidine-1-carboxylate

To a solution of methyl(triphenyl)phosphonium; bromide (2.66 g, 7.46mmol, 1.3 eq) in THE (10 mL) was cooled to −78° C. then added n-BuLi(2.5 M, 2.98 mL, 1.3 eq) dropwise under N₂ atmosphere. The mixture wasstirred at 0° C. for 0.5 h under N₂ atmosphere. The mixture was cooledto −78° C. and a solution of tert-butyl(3R)-3-formylpiperidine-1-carboxylate (1.4 g, 5.74 mmol, 1 eq) in THF (5mL) was added slowly. The mixture was stirred at 27° C. for 4 h under N₂atmosphere. The reaction mixture was diluted with water (50 mL) thenextracted with EtOAc (30 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=5/1, R_(f)=0.65) to yieldtert-butyl (3S)-3-vinylpiperidine-1-carboxylate (400 mg, 1.70 mmol,29.7% yield, 90.0% purity) as a colorless gum. H NMR (400 MHz, DMSO-d₆)δ ppm 5.72 (d, J=6.5, 10.6, 17.4 Hz, 1H), 5.11-4.95 (m, 2H), 3.77 (d,J=13.2 Hz, 2H), 2.81-2.64 (m, 1H), 2.05 (d, J=5.9 Hz, 1H), 1.75 (d,J=11.7 Hz, 1H), 1.65-1.53 (m, 2H), 1.39 (s, 9H), 0.87-0.82 (m, 2H).

Step 3: tert-Butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl (3S)-3-vinylpiperidine-1-carboxylate (360mg, 1.70 mmol, 1 eq) and dibromomethanone oxime (380.13 mg, 1.87 mmol,1.1 eq) in EtOAc (15 mL) was added NaHCO₃ (1.43 g, 17.04 mmol, 10 eq).The mixture was stirred at 25° C. for 12 h under N₂ atmosphere. Thereaction mixture was diluted with water (150 mL), extracted with EtOAc(50 mL×3). The combined organic layers were dried over Na₂SO₄, filteredand the filtrate was concentrated to yield a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=3/1, R_(f)=0.40) to yield tert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (360mg, 1.03 mmol, 60.2% yield, 95.0% purity) as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 4.50 (s, 1H), 3.83 (s, 1H), 3.25 (dt, J=10.6, 17.9 Hz,1H), 3.00 (dd, J=8.4, 16.5 Hz, 1H), 2.75 (s, 1H), 1.57 (s, 6H), 1.46 (s,10H), 1.27 (t, J=7.1 Hz, 1H).

Step 4: 3-Bromo-5-[(3R)-3-piperidyl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (320mg, 960.32 μmol, 1 eq) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol,3 mL, 42.19 eq) at 30° C. The mixture was stirred at 30° C. for 1 h. TLC(PE/EtOAc=2/1, R_(f)=0.05) showed the starting material was consumedcompletely. The reaction mixture was concentrated under reduced pressureto yield 3-bromo-5-[(3R)-3-piperidyl]-4,5-dihydroisoxazole (330 mg,950.66 μmol, 99.0% yield, N/A purity, TFA) as a colorless gum, which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.49 (br s, 1H), 4.69-4.60 (m, 1H), 4.59-4.49 (m, 1H), 3.62(d, J=10.5 Hz, 1H), 3.36 (td, J=10.1, 17.5 Hz, 2H), 3.02 (td, J=7.4,17.4 Hz, 2H), 2.88-2.72 (m, 2H), 2.18 (d, J=10.3 Hz, 2H), 1.94 (dd,J=3.2, 6.6 Hz, 1H).

Step 5:(5S)-3-Bromo-5-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazoleand(5R)-3-bromo-5-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole

To a solution 3-bromo-5-[(3R)-3-piperidyl]-4,5-dihydroisoxazole (330 mg,950.66 μmol, 1 eq, TFA) and DIEA (614.33 mg, 4.75 mmol, 827.94 μL, 5 eq)in DCM (10 mL) was added 1-(bromomethyl)-3-(trifluoromethyl)benzene (275mg, 1.15 mmol, 175.16 μL, 1.21 eq) at 30° C. for 12 h. The reactionmixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 5/1, TLC: PE/EtOAc=3/1,R_(f)=0.40). The desired compound was concentrated under reducedpressure to yield a residue (120 mg with 90% purity) which was separatedby chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, Sum); mobilephase: [0.1% NH₃:H₂O/EtOH]; B %: 10%-10%) to yield peak1 and peak 2.Peak 1 was concentrated under reduced pressure to yield a residue whichwas dissolved in MeCN (15 mL) and water (15 mL) and lyophilized to yield(5S)-3-bromo-5-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole(55.30 mg, 140.08 μmol, 14.7% yield, 99.1% purity, SFC: R_(t)=1.849,Dr=97.02%, [α]^(28.4) _(D)=−81.48 (CHCl₃, c=0.054 g/100 mL)) ascolorless oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.58 (s, 1H), 7.55-7.48 (m,2H), 7.46-7.42 (m, 1H), 4.66-4.55 (m, 1H), 3.60-3.46 (m, 2H), 3.15 (dd,J=10.7, 17.1 Hz, 1H), 2.91 (dd, J=9.0, 17.1 Hz, 1H), 2.75-2.60 (m, 2H),2.15-2.05 (m, 1H), 2.02-1.94 (m, 1H), 1.95-1.85 (m, 1H), 1.84-1.72 (m,2H), 1.63-1.59 (m, 1H), 1.28-1.20 (m, 1H); ES-LCMS m/z 391.1, 393.1[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (15 mL) and water (15 mL) andlyophilized to yield(5R)-3-bromo-5-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-piperidyl]-4,5-dihydroisoxazole(33.70 mg, 83.99 μmol, 8.8% yield, 97.5% purity, SFC: R_(t)=2.141,Dr=97.22%, [α]^(28.5) _(D)=+76.19 (CHCl₃, c=0.021 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.57 (s, 1H), 7.52 (d, J=7.5 Hz,2H), 7.46-7.41 (m, 1H), 4.57-4.46 (m, 1H), 3.65-3.47 (m, 2H), 3.20 (dd,J=10.5, 17.2 Hz, 1H), 3.05-2.91 (m, 2H), 2.80-2.70 (m, 1H), 2.05-1.88(m, 3H), 1.74-1.60 (m, 3H), 1.57 (s, 9H), 1.06 (d, J=9.3 Hz, 1H);ES-LCMS m/z 391.1, 393.1 [M+H]⁺.

I-111 & I-112

Step 1: N-(2-Methyl-5-vinyl-phenyl)-4-(trifluoromethyl)pyridin-2-amine

To a stirred solution of 2-methyl-5-vinyl-aniline (300 mg, 2.07 mmol, 1eq) and 2-bromo-4-(trifluoromethyl)pyridine (468.31 mg, 2.07 mmol, 1 eq)in toluene (9 mL) was added Pd₂(dba)₃ (189.76 mg, 207.22 μmol, 0.1 eq),RuPhos (193.39 mg, 414.45 μmol, 0.2 eq), t-BuONa (398.30 mg, 4.14 mmol,2 eq). The reaction mixture was stirred at 100° C. for 12 h. The mixturewas filtered through a celite pad and the filtrate was concentrated toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.65) to yieldN-(2-methyl-5-vinyl-phenyl)-4-(trifluoromethyl)pyridin-2-amine (470 mg,871.52 μmol, 42.0% yield, 51.6% purity) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.26 (d, J=5.1 Hz, 1H), 7.63 (s, 1H), 7.27 (s, 1H),7.21-7.15 (m, 2H), 6.99 (s, 1H), 6.93 (d, J=4.9 Hz, 1H), 6.69-6.63 (m,1H), 5.79-5.71 (m, 1H), 5.26-5.20 (m, 1H), 2.19 (s, 3H); ES-LCMS m/z279.0 [M+H]⁺.

Step 2:N-[5R-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2-methyl-phenyl]-4-(trifluoromethyl)pyridin-2-amine&N-[5S-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-methyl-phenyl]-4-(trifluoromethyl)pyridin-2-amine

To a solution ofN-(2-methyl-5-vinyl-phenyl)-4-(trifluoromethyl)pyridin-2-amine (240 mg,445.03 μmol, 1 eq) in EtOAc (6 mL) was added dibromomethanone oxime(180.53 mg, 890.07 μmol, 2 eq) and NaHCO₃ (373.87 mg, 4.45 mmol, 10 eq).The mixture was bubbled with N₂ for 2 min and stirred at 25° C. for 12 hunder microwave. The mixture was filtered through a celite pad, and thefiltrate was concentrated to yield a residue which was purified bypreparative HPLC (column: Agela DuraShell C18 150*25 mm*5 μm; mobilephase: [water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 49%-79%, 10 min).The desired fraction was lyophilized to yield the compound which wasseparated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm);mobile phase: [0.10% NH₃H₂O EtOH]; B %: 25%-25%, min) to yield Peak 1and Peak 2. Peak 1 was concentrated under reduced pressure to yield aresidue which was lyophilized to yieldN-[5R-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-methyl-phenyl]-4-(trifluoromethyl)pyridin-2-amine(27.01 mg, 67.49 μmol, 15.1% yield, 100% purity, SFC: R_(t)=1.113 min,ee=97.88%, [α]^(28.3) _(D)=+156.25, MeOH, c=0.032 g/100 mL) as yellowoil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.73 (s, 1H), 8.26 (d, J=5.1 Hz,1H), 7.59 (d, J=1.2 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.08-7.02 (m, 2H),6.95 (d, J=5.1 Hz, 1H), 5.65 (dd, J=9.3, 10.5 Hz, 1H), 3.75 (dd, J=10.8,17.6 Hz, 1H), 3.27 (dd, J=9.0, 17.4 Hz, 1H), 2.21 (s, 3H); ES-LCMS m/z400.0, 402.1 [M+H]⁺. Peak 1 was concentrated under reduced pressure toyield a residue which was lyophilized to yieldN-[5S-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-methyl-phenyl]-4-(trifluoromethyl)pyridin-2-amine(18.97 mg, 47.40 μmol, 10.6% yield, 100% purity, SFC: R_(t)=1.290 min,ee=100%, [α]²⁸0.0_(D)=−133.33, MeOH, c=0.033 g/100 mL) as yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.74 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 7.60(d, J=1.5 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.09-7.03 (m, 2H), 6.96 (d,J=5.1 Hz, 1H), 5.66 (dd, J=9.3, 10.5 Hz, 1H), 3.76 (dd, J=10.9, 17.5 Hz,1H), 3.28 (dd, J=9.2, 17.5 Hz, 1H), 2.22 (s, 3H); ES-LCMS m/z 400.0,402.1 [M+H]⁺.

I-113 & I-114

Step 1:(5R)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-pyrimidin-5-yloxy-4,5-dihydroisoxazole& &(5S)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-pyrimidin-5-yloxy-4,5-dihydroisoxazole

To a stirred solution of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(250 mg, 487.27 μmol, 1 eq) and pyrimidin-5-ol (51.50 mg, 536.00 μmol,1.1 eq) in DMSO (5 mL) was added 2-Picolinic acid (4.80 mg, 38.98 μmol,0.08 eq), K₃PO₄ (175.84 mg, 828.36 μmol, 1.7 eq) and CuI (4.64 mg, 24.36μmol, 0.05 eq). The reaction mixture was stirred at 120° C. for 12 hunder N₂ atmosphere. The reaction mixture was diluted with H₂O (10 mL)and extracted with EtOAc (20 mL×3). The combined organic layers werewashed with brine (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=2/1, R_(f)=0.45) to yield crude product which was separated bySFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase:[0.1% NH₃.H₂O IPA]; B %: 25%-25%, min) to yield Peak 1 and Peak 2. Peak1 was concentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-pyrimidin-5-yloxy-4,5-dihydroisoxazole(17.98 mg, 43.29 μmol, 8.9% yield, 100% purity, SFC: R_(t)=0.924 min,ee=99.92%, [α]^(27.4) _(D)=+28.571 (MeOH, c=0.035 g/100 mL)) as red oil.¹H NMR (500 MHz, MeOD) δ ppm 9.02 (s, 1H), 8.91-8.85 (m, 2H), 7.55-7.48(m, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.26 (dd,J=1.2, 7.9 Hz, 1H), 7.15-7.09 (m, 2H), 7.07 (s, 1H), 5.75 (t, J=9.8 Hz,1H), 3.69 (dd, J=10.4, 16.8 Hz, 1H), 3.28 (d, J=9.5 Hz, 1H), 2.21 (s,3H); ES-LCMS m/z 416.0 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(40 mL) and lyophilized to yield(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-pyrimidin-5-yloxy-4,5-dihydroisoxazole(24.36 mg, 58.65 μmol, 12.0% yield, 100% purity, SFC: R_(t)=1.117 min,ee=94.82%, [α]^(27.4) _(D)=−16.667 (MeOH, c=0.024 g/100 mL)) as red oil.¹H NMR (500 MHz, MeOD) δ ppm 9.02 (s, 1H), 8.88 (s, 2H), 7.54-7.49 (m,1H), 7.39 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.26 (dd, J=1.5,7.8 Hz, 1H), 7.15-7.09 (m, 2H), 7.07 (d, J=1.4 Hz, 1H), 5.75 (t, J=9.8Hz, 1H), 3.69 (dd, J=10.3, 16.9 Hz, 1H), 3.30-3.26 (m, 1H), 2.21 (s,3H); ES-LCMS m/z 416.0 [M+H]⁺.

I-55

Step 1: tert-Butyl (3R)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate

To a solution of tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate(500.00 mg, 2.68 mmol, 455.37 μL, 1 eq) and Et₃N (543.30 mg, 5.37 mmol,747.32 μL, 2.0 eq) in DCM (5 mL) was added prop-2-enoyl chloride (267.27mg, 2.95 mmol, 240.78 μL, 1.1 eq). The mixture was stirred under N₂atmosphere at 0° C. for 30 min. TLC (PE/EtOAc=3/1, R_(f)=0.60) showedone main spot formed. The mixture was quenched with H₂O (20 mL) andextracted with EtOAc (30 mL×3). The combined organic layer was driedover Na₂SO₄, filtrated and concentrated to give a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 3/1,TLC: PE/EtOAc=3/1, R_(f)=0.60) to yield tert-butyl(3R)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate (200 mg, 790.68μmol, 29.5% yield, 95.0% purity) as a faint yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.32 (d, J=5.1 Hz, 1H), 6.27-6.17 (m, 1H), 6.13-6.05(m, 1H), 5.59 (dd, J=2.2, 10.0 Hz, 1H), 4.29-4.20 (m, 1H), 3.53-3.40 (m,1H), 3.32-3.22 (m, 2H), 3.10-3.01 (m, 1H), 2.03 (td, J=6.8, 13.1 Hz,1H), 1.74 (d, J=5.1 Hz, 1H), 1.39 (s, 9H); ES-LCMS m z no desired MSfound.

Step 2: N-[(3R)-Pyrrolidin-3-yl]prop-2-enamide

To a solution of tert-butyl(3R)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate (200 mg, 749.07μmol, 1 eq) in DCM (5 mL) was added TFA (450 mg, 3.95 mmol, 1 mL, 5.27eq). The mixture was stirred at 25° C. for 1 h. The reaction mixture wasconcentrated under reduced pressure to yieldN-[(3R)-pyrrolidin-3-yl]prop-2-enamide (100 mg, 355.22 μmol, 47.4%yield, 90.3% purity, TFA) as a yellow solid, which was used in the nextstep without further purification. 1H NMR (400 MHz, DMSO-d₆) δ ppm6.27-6.07 (m, 2H), 5.64 (dd, J=2.6, 9.7 Hz, 1H), 4.42-4.27 (m, 1H),3.46-3.37 (m, 1H), 3.35-3.16 (m, 2H), 3.11-2.97 (m, 1H), 2.21-2.08 (m,1H), 1.86 (qd, J=6.6, 13.1 Hz, 1H); ES-LCMS m z no desired MS found.

Step 3:N-[(3R)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]prop-2-enamide

To a solution of N-[(3R)-pyrrolidin-3-yl]prop-2-enamide (100 mg, 644.16μmol, 1 eq, TFA) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (180 mg,753.04 μmol, 116.13 μL, 1.17 eq) in THE (3 mL) was added K₂CO₃ (90.09mg, 651.83 μmol, 1.01 eq). The mixture was stirred at 60° C. for 12 h.TLC (PE/EtOAc=3/1, R_(f)=0.47) showed one main spot formed. The reactionmixture was quenched with H₂O (10 mL) and extracted with EtOAc (10mL×3). The combined organic layers dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm;mobile phase: [water (10 mm NH₄HCO₃)-ACN]; B %: 35%-65%, 10 min) andthen lyophilized to yieldN-[(3R)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]prop-2-enamide(17.18 mg, 56.52 μmol, 8.8% yield, 98.1% purity) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.58 (d, J=8.2 Hz, 2H), 7.43 (d, J=7.8 Hz,2H), 6.27 (dd, J=1.6, 16.8 Hz, 1H), 6.10-6.01 (m, 1H), 5.64 (dd, J=1.4,10.4 Hz, 1H), 4.64-4.51 (m, 1H), 3.73-3.61 (m, 2H), 2.93-2.84 (m, 1H),2.68-2.55 (m, 2H), 2.40-2.24 (m, 2H), 1.73-1.67 (m, 1H); ES-LCMS m/z299.2 [M+H]⁺.

I-56

Step 1: tert-Butyl N-[4-[4-(trifluoromethyl)anilino]cyclohexyl]carbamate

To a stirred solution of tert-butyl N-(4-aminocyclohexyl)carbamate (200mg, 933.26 μmol, 1 eq) in DCM (10 mL) was added DIEA (361.84 mg, 2.80mmol, 487.66 μL, 3 eq), Cu(OAc)₂ (339.01 mg, 1.87 mmol, 2 eq) and[4-(trifluoromethyl)phenyl]boronic acid (186.11 mg, 979.92 μmol, 1.05eq). The reaction mixture was at 29° C. for 48 h under oxygen atmosphere(15 psi). TLC (PE/EtOAc=3/1, R_(f)=0.50) showed one new spot wasdetected. The reaction mixture was concentrated to yield a residue whichwas purified by preparative TLC (PE/EtOAc=3/1, TLC: PE/EtOAc=3/1,R_(f)=0.50) to yield tert-butylN-[4-[4-(trifluoromethyl)anilino]cyclohexyl]carbamate (100 mg, 251.12μmol, 26.9% yield, 90.0% purity) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.32 (d, J=8.3 Hz, 2H), 6.79 (d, J=7.1 Hz, 1H), 6.63 (d,J=8.3 Hz, 2H), 6.18 (d, J=7.3 Hz, 1H), 3.19 (d, J=10.5 Hz, 2H), 1.95 (d,J=10.8 Hz, 2H), 1.79 (d, J=10.5 Hz, 2H), 1.38 (s, 9H), 1.30-1.16 (m,4H); ES-LCMS m/z 359.2 [M+H]⁺.

Step 2: N4-[4-(Trifluoromethyl)phenyl]cyclohexane-1,4-diamine

To a stirred solution of tert-butylN-[4-[4-(trifluoromethyl)anilino]cyclohexyl]carbamate (100 mg, 251.12μmol, 1 eq) in DCM (10 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL,161.35 eq). The reaction mixture was at 29° C. for 1 h. TLC(PE/EtOAc=3/1) showed the starting material was consumed completely. Thereaction mixture was concentrated to yieldN4-[4-(trifluoromethyl)phenyl]cyclohexane-1,4-diamine (100 mg, 185.06μmol, 73.7% yield, 90.0% purity, 2TFA) as yellow oil which was used inthe next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.79 (s, 3H), 7.35 (d, J=8.6 Hz, 2H), 6.67 (d, J=8.6 Hz, 2H),3.28-3.16 (m, 1H), 3.02 (s, 1H), 2.03 (s, 2H), 1.95 (d, J=11.0 Hz, 2H),1.43 (q, J=11.8 Hz, 2H), 1.28-1.19 (m, 2H).

Step 3: N-[4-[4-(Trifluoromethyl)anilino]cyclohexyl]prop-2-enamide

To a stirred solution ofN4-[4-(trifluoromethyl)phenyl]cyclohexane-1,4-diamine (100 mg, 185.06μmol, 1 eq, 2TFA) in DCM (10 mL) was added DIEA (143.51 mg, 1.11 mmol,193.40 μL, 6 eq) and prop-2-enoyl chloride (15.07 mg, 166.55 μmol, 13.58μL, 0.9 eq). The reaction mixture was stirred at 29° C. for 20 min. Thereaction mixture was concentrated to yield a residue which was purifiedby preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobilephase: [water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 38%-68%, 10 min).The desired fraction was lyophilized to yieldN-[4-[4-(trifluoromethyl)anilino]cyclohexyl]prop-2-enamide (26.14 mg,81.18 μmol, 43.9% yield, 97.0% purity) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.02 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.66 (d,J=8.8 Hz, 2H), 6.26-6.17 (m, 2H), 6.10-6.02 (m, 1H), 5.59-5.53 (m, 1H),3.68-3.54 (m, 1H), 3.28-3.19 (m, 1H), 1.98 (d, J=12.2 Hz, 2H), 1.85 (d,J=11.5 Hz, 2H), 1.38-1.18 (m, 4H); ES-LCMS m/z 313.2 [M+H]⁺.

I-57

Step 1: tert-Butyl (3S)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate

A solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (500.00mg, 2.68 mmol, 1 eq) and Et₃N (545.25 mg, 5.39 mmol, 750 μL, 2.01 eq) inDCM (5 mL) was stirred at 28° C. The mixture was cooled to 0° C. andthen prop-2-enoyl chloride (290 mg, 3.20 mmol, 261.26 μL, 1.19 eq) wasadded dropwise at 0° C. The resulting mixture was stirred at 28° C. for12 h. The mixture was diluted with water (20 mL) and extracted withEtOAc (25 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield tert-butyl(3S)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate (560 mg, 2.10 mmol,78.1% yield, 90.0% purity) as a yellow solid, which was used in the nextstep without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm6.23-6.13 (m, 1H), 6.11-6.02 (m, 1H), 5.56 (dd, J=2.2, 10.0 Hz, 1H),4.26-4.16 (m, 1H), 3.50-3.35 (m, 2H), 3.29-3.25 (m, 2H), 3.10-2.97 (m,1H), 2.07-1.97 (m, 1H), 1.76-1.66 (m, 1H), 1.36 (s, 9H); ES-LCMS m/z241.2 [M+H]⁺.

Step 2: N-[(3S)-Pyrrolidin-3-yl]prop-2-enamide

A solution of tert-butyl(3S)-3-(prop-2-enoylamino)pyrrolidine-1-carboxylate (560 mg, 2.10 mmol,1 eq) in DCM (6 mL) and TFA (2 mL) was stirred at 28° C. for 12 h. Thereaction mixture was diluted with water (20 mL), neutralized with NaHCO₃until pH=7 and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield N-[(3S)-pyrrolidin-3-yl]prop-2-enamide (600 mg, 1.89mmol, 90.0% yield, 80.0% purity, TFA) as a yellow oil, which was used inthe next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.99-8.85 (m, 1H), 8.44 (d, J=4.7 Hz, 1H), 6.23-6.14 (m, 1H), 6.13(d, J=2.7 Hz, 1H), 5.63 (dd, J=2.5, 9.6 Hz, 1H), 4.33 (td, J=6.1, 12.1Hz, 1H), 3.42-3.33 (m, 1H), 3.30-3.20 (m, 2H), 3.06-2.97 (m, 1H),2.23-2.04 (m, 1H), 1.85 (td, J=6.5, 13.2 Hz, 1H).

Step 3:N-[(3S)-1-[[4-(Trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]prop-2-enamide

To a solution of N-[(3S)-pyrrolidin-3-yl]prop-2-enamide (300 mg, 944.12μmol, 1 eq, TFA) in DCM (5 mL) was added DIEA (600 mg, 4.64 mmol, 808.63μL, 4.92 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (180 mg,753.04 μmol, 116.13 μL, 7.98e-1 eq). The mixture was stirred at 28° C.for 12 h. The mixture was diluted with water (20 mL) and extracted withEtOAc (25 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield the residuewhich was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 um; mobile phase: [water (0.05% NH₃.H₂O+10 mM/NH₄HCO₃)-ACN];B %: 34%-49%, 14 min) to yieldN-[(3S)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]prop-2-enamide(26.17 mg, 85.08 μmol, 9.0% yield, 97.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.59 (d, J=8.1 Hz, 2H), 7.44 (d, J=7.8 Hz,2H), 6.28 (dd, J=1.5, 16.9 Hz, 1H), 6.13-6.00 (m, 1H), 5.89 (br s, 1H),5.65 (dd, J=1.2, 10.3 Hz, 1H), 4.65-4.47 (m, 1H), 3.74-3.60 (m, 2H),2.96-2.83 (m, 1H), 2.70-2.55 (m, 2H), 2.43-2.21 (m, 2H), 1.73-1.64 (m,1H); ES-LCMS m/z 299.2 [M+H]⁺.

I-115 & I-116

Step 1:5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole

To a solution of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(300 mg, 584.72 μmol, 1 eq) in DMF (10 mL) was added Cs₂CO₃ (571.54 mg,1.75 mmol, 3 eq) and 4H-1,2,4-triazole (121.15 mg, 1.75 mmol, 3 eq). Themixture was stirred at 80° C. for 2 h. The reaction mixture was quenchedby addition of water (50 mL), extracted with EtOAc (30 mL×3). Theorganic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered, concentrated to yield a residue which was purified bypreparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobilephase: [water (0.05% HCl)-ACN]; B %: 58%-78%, 10 min), followed bylyophilization to yield5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole(150 mg, 384.33 μmol, 65.7% yield, 99.5% purity) as colorless oil. ¹HNMR (400 MHz, CD₃OD) δ ppm 9.04 (s, 1H), 8.19 (s, 1H), 7.52 (t, J=7.9Hz, 1H), 7.46-7.23 (m, 3H), 7.18-7.05 (m, 2H), 5.94-5.82 (m, 1H), 4.06(dd, J=10.9, 17.2 Hz, 2H), 3.58 (dd, J=9.3, 17.4 Hz, 1H), 2.22 (s, 3H);ES-LCMS m/z 389.0 [M+H]⁺.

Step 2:(5R)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole&(5S)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole

5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole(150.00 mg, 384.33 μmol, 1 eq) was separated by SFC (column:Phenomenex-Cellulose-2 (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃.H₂OMEOH]; B %: 40%-40%, min, Peak1, 0.805, Peak2, 0.912). Peak 1 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and H₂O (5 mL) and lyophilized to yield(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole(18.04 mg, 45.66 μmol, 11.9% yield, 98.3% purity, SFC: R_(t)=0.806,ee=100%, [α]^(29.0) _(D)=+139.753 (MeOH, c=0.05 g/100 mL)) as colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.81 (s, 1H), 8.07 (s, 1H), 7.45-7.39(m, 1H), 7.37-7.30 (m, 2H), 7.21-7.14 (m, 2H), 7.06-6.98 (m, 2H), 5.82(t, J=10.0 Hz, 1H), 3.98 (dd, J=10.9, 17.5 Hz, 1H), 3.57 (dd, J=9.0,17.6 Hz, 1H), 2.24 (s, 3H); ES-LCMS m/z 389.0 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and H₂O (5 mL) and lyophilized to yield(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(1,2,4-triazol-1-yl)-4,5-dihydroisoxazole(23.13 mg, 57.89 μmol, 15.0% yield, 97.2% purity, SFC: R_(t)=0.912,ee=97.06%, [α]^(28.9) _(D)=−197.229 (MeOH, c=0.0575 g/100 mL)) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ=8.81 (s, 1H), 8.07 (s, 1H),7.46-7.39 (m, 1H), 7.36-7.30 (m, 2H), 7.21-7.13 (m, 2H), 7.06-6.98 (m,2H), 5.82 (dd, J=9.3, 10.5 Hz, 1H), 3.98 (dd, J=11.0, 17.6 Hz, 1H), 3.57(dd, J=9.0, 17.6 Hz, 1H), 2.24 (s, 3H); ES-LCMS m/z 389.0 [M+H]⁺.

I-117 & I-118

Step 1: 5-Bromo-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of 5-bromo-2-methyl-aniline (1 g, 5.37 mmol, 1 eq) and[3-(trifluoromethyl)phenyl]boronic acid (2.04 g, 10.75 mmol, 2 eq) inDCM (20 mL) was added Cu(OAc)₂ (1.95 g, 10.75 mmol, 2 eq) and DIEA (2.78g, 21.50 mmol, 3.74 mL, 4 eq). The mixture was stirred at 28° C. for 12h under O₂ (15 psi) atmosphere which was filtered through a pad ofcelite and the filtrate was concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 2/1,TLC: PE/EtOAc=5/1, R_(f)=0.40) to yield5-bromo-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline (1.2 g, 3.33 mmol,61.9% yield, 91.5% purity) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.00 (s, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.29 (d, J=1.7 Hz, 1H),7.21-7.08 (m, 5H), 2.15 (s, 3H); ES-LCMS m z329.9, 331.9 [M+H]⁺.

Step 2: 5-Isopropenyl-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of 5-bromo-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline(1 g, 2.03 mmol, 1 eq),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (409.84 mg, 2.44mmol, 1.2 eq) in 1,4-dioxane (6 mL) and water (2 mL) was added Cs₂CO₃(1.99 g, 6.10 mmol, 3 eq) and Pd(dppf)Cl₂ (148.72 mg, 203.25 μmol, 0.1eq). The mixture was bubbled with N₂ for 2 min then stirred at 100° C.for 30 min under microwave (2 bar). The reaction mixture was dilutedwith water (150 mL) then extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=5/1,R_(f)=0.65) to yield5-isopropenyl-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline (590 mg,1.36 mmol, 67.0% yield, 67.2% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.95 (s, 1H), 7.38-7.35 (m, 1H), 7.30 (d, J=1.7 Hz, 1H),7.24-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.05 (d, J=5.8 Hz, 2H), 7.03-6.98(m, 2H), 5.04 (s, 1H), 2.17 (s, 3H), 2.05 (s, 3H); ES-LCMS m/z 347.0,292.2 [M+H]⁺.

Step 3:5-[(5R)-3-Bromo-5-methyl-4H-isoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline&5-[(5S)-3-Bromo-5-methyl-4H-isoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of5-isopropenyl-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline (350 mg,1.20 mmol, 1 eq) and dibromomethanone oxime (365.55 mg, 1.80 mmol, 1.5eq) in EtOAc (10 mL) was added NaHCO₃ (1.01 g, 12.01 mmol, 10 eq). Themixture was stirred at 25° C. for 12 h under N₂ atmosphere. The reactionmixture was diluted with water (50 mL) then extracted with EtOAc (30mL×3). The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated to yield a residue which was purified byflash silica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=5/1, R_(f)=0.65) to yield the compound which was separated bySFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm); mobile phase:[0.1% NH₃H₂O EtOH]; B %: 30%-30%, min) to yield Peak 1 and Peak 2. Peak1 was concentrated under reduced pressure to yield a residue which waslyophilized to yield5-[(5R)-3-bromo-5-methyl-4H-isoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline(80 mg, 193.60 μmol, 16.1% yield, 100% purity, SFC: R_(t)=4.340 min,ee=99.2%, [α]^(29.3) _(D)=+66.67, MeOH, c=0.069 g/100 mL) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ ppm 7.38-7.32 (m, 1H), 7.30-7.27 (m, 1H), 7.25(d, J=7.8 Hz, 1H), 7.15-7.10 (m, 2H), 7.07-7.02 (m, 2H), 5.56 (s, 1H),3.38-3.26 (m, 2H), 2.25 (s, 3H), 1.75 (s, 3H); ES-LCMS m/z 413.1, 415.1[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield aresidue which was lyophilized to yield5-[(5S)-3-bromo-5-methyl-4H-isoxazol-5-yl]-2-methyl-N-[3-(trifluoromethyl)phenyl]aniline(62 mg, 147.04 μmol, 12.2% yield, 98.0% purity SFC: R_(t)=5.143 min,ee=98.1% [α]^(29.3) _(D)=−69.10, MeOH, c=0.055 g/100 mL) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ ppm 7.38-7.32 (m, 1H), 7.30 (s, 1H), 7.25 (d,J=8.1 Hz, 1H), 7.15-7.10 (m, 2H), 7.05 (dd, J=2.1, 7.7 Hz, 2H), 5.57 (s,1H), 3.39-3.23 (m, 2H), 2.25 (s, 3H), 1.75 (s, 3H); ES-LCMS m/z 413.1,415.1 [M+H]⁺

I-58

Step 1: tert-Butyl N-[4-[4-(trifluoromethyl)anilino]cyclohexyl]carbamate

To a stirred solution of tert-butyl N-(4-aminocyclohexyl)carbamate (300mg, 1.40 mmol, 1 eq) in DCM (10 mL) was added DIEA (542.76 mg, 4.20mmol, 731.48 μL, 3 eq), Cu(OAc)₂ (508.52 mg, 2.80 mmol, 2 eq) and[4-(trifluoromethyl)phenyl]boronic acid (319.05 mg, 1.68 mmol, 1.2 eq).The reaction mixture was at 29° C. for 48 h under oxygen atmosphere (15psi). The reaction mixture was filtered and the filtrate wasconcentrated to yield a residue which was purified by preparative TLC(PE/EtOAc=3/1, TLC: PE/EtOAc=3/1, R_(f)=0.40) to yield tert-butylN-[4-[4-(trifluoromethyl)anilino]cyclohexyl]carbamate (200 mg, 502.24μmol, 35.9% yield, 90.0% purity) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.33 (d, J=8.6 Hz, 2H), 6.74 (s, 1H), 6.67 (d, J=8.6 Hz,2H), 6.15 (d, J=6.6 Hz, 1H), 3.48-3.36 (m, 2H), 1.70-1.49 (m, 8H), 1.38(s, 9H); ES-LCMS m/z 359.2 [M+H]⁺.

Step 2: N4-[4-(Trifluoromethyl)phenyl]cyclohexane-1,4-diamine

To a stirred solution of tert-butylN-[4-[4-(trifluoromethyl)anilino]cyclohexyl]carbamate (200 mg, 502.23μmol, 1 eq) in DCM (10 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL,80.68 eq). The reaction mixture was at 29° C. for 1 h. TLC(PE/EtOAc=3/1) showed the starting material was consumed completely. Thereaction mixture was concentrated to yieldN4-[4-(trifluoromethyl)phenyl]cyclohexane-1,4-diamine (160 mg, 296.10μmol, 59.0% yield, 90.0% purity, 2TFA) as yellow oil which was used inthe next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.76 (s, 3H), 7.37 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 3.14(s, 2H), 1.88-1.56 (m, 8H).

Step 3: N-[4-[4-(Trifluoromethyl)anilino]cyclohexyl]prop-2-enamide

To a stirred solution ofN4-[4-(trifluoromethyl)phenyl]cyclohexane-1,4-diamine (160 mg, 296.10μmol, 1 eq, 2TFA) in DCM (10 mL) was added DIEA (229.61 mg, 1.78 mmol,309.45 μL, 6 eq) and prop-2-enoyl chloride (24.12 mg, 266.49 μmol, 21.73μL, 0.9 eq). The reaction mixture was stirred at 29° C. for 1 h. Thereaction mixture was concentrated to yield a residue which was purifiedby preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobilephase: [water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 50%-80%, 10 min).The desired fraction was lyophilized to yieldN-[4-[4-(trifluoromethyl)anilino]cyclohexyl]prop-2-enamide (22.3 mg,71.40 μmol, 24.1% yield, 100.0% purity) as white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.97 (d, J=7.0 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 6.69 (d,J=8.7 Hz, 2H), 6.30 (dd, J=10.2, 17.1 Hz, 1H), 6.24 (d, J=6.4 Hz, 1H),6.07 (dd, J=2.1, 17.1 Hz, 1H), 5.55 (dd, J=2.3, 10.1 Hz, 1H), 3.77 (s,1H), 3.40 (s, 1H), 1.72-1.58 (m, 8H); ES-LCMS m/z 313.2 [M+H]⁺.

I-147 & I-148

Step 1: tert-Butyl (3R)-3-formylpyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.5 g, 7.45 mmol, 1 eq)in DCM (50 mL) was added Dess-Martin periodinane (4.11 g, 9.69 mmol,3.00 mL, 1.3 eq) at 30° C. The mixture was stirred at 30° C. for 12 h.TLC (PE/EtOAc=1/1, R_(f)=0.70) showed about 50% of the starting materialwas consumed. The mixture was filtered. The filtrate was concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 1/1, TLC:PE/EtOAc=1/1, R_(f)=0.70) to yield tert-butyl(3R)-3-formylpyrrolidine-1-carboxylate (800 mg, 4.02 mmol, 53.9% yield,N/A purity) as a colorless gum. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.70 (d,J=1.6 Hz, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 1H), 3.48-3.40 (m, 2H),3.10-3.00 (m, 1H), 2.26-2.16 (m, 2H), 1.47 (s, 9H).

Step 2: tert-Butyl (3S)-3-vinylpyrrolidine-1-carboxylate

To a solution of methyl(triphenyl)phosphonium; bromide (1.72 g, 4.82mmol, 1.2 eq) in THF (20 mL) was added n-BuLi (2.5 M, 2.25 mL, 1.4 eq)under N₂ atmosphere at −70° C. The mixture was stirred under N₂atmosphere at 0° C. for 0.5 h. The mixture was cooled to −70° C. Asolution of tert-butyl (3R)-3-formylpyrrolidine-1-carboxylate (800 mg,4.02 mmol, 1 eq) in THE (5 mL) was added. The mixture was warmed to 25°C. slowly and stirred under N₂ atmosphere at 25° C. for 2 h. TLC(PE/EtOAc=10/1, R_(f)=0.60) showed the starting material was consumedcompletely. The reaction mixture was diluted with H₂O (50 mL) andextracted with EtOAc (50 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=10/1, R_(f)=0.60) to yieldtert-butyl (3S)-3-vinylpyrrolidine-1-carboxylate (220 mg, 1.12 mmol,27.8% yield, N/A purity) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm5.78 (ddd, J=7.6, 10.3, 17.3 Hz, 1H), 5.16-5.08 (m, 1H), 5.04 (d, J=10.6Hz, 1H), 3.55-3.45 (m, 2H), 3.35-3.25 (m, 1H), 3.10-3.00 (m, 1H), 2.79(d, J=7.8 Hz, 1H), 2.01 (tdd, J=3.4, 6.5, 12.6 Hz, 1H), 1.77-1.66 (m,1H), 1.47 (s, 9H).

Step 3: tert-Butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate

A mixture of tert-butyl (3S)-3-vinylpyrrolidine-1-carboxylate (200 mg,1.01 mmol, 1 eq), dibromomethanone oxime (250 mg, 1.23 mmol, 1.22 eq)and NaHCO₃ (850 mg, 10.12 mmol, 9.98 eq) in EtOAc (15 mL) was stirred at25° C. for 2 h. TLC (PE/EtOAc=2/1, R_(f)=0.33) showed the startingmaterial was consumed completely. The reaction mixture was diluted withH₂O (30 mL) and extracted with EtOAc (30 mL×3). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=2/1, R_(f)=0.33) to yieldtert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (210mg, 636.20 μmol, 62.8% yield, 96.7% purity) as a colorless gum. ¹H NMR(400 MHz, CDCl₃) δ ppm 4.66-4.56 (m, 1H), 3.63-3.44 (m, 2H), 3.31 (dd,J=10.6, 17.2 Hz, 2H), 3.24-3.03 (m, 1H), 2.94 (dd, J=8.4, 17.0 Hz, 1H),2.46 (dd, J=7.8, 16.4 Hz, 1H), 2.10-1.94 (m, 1H), 1.88-1.78 (m, 1H),1.46 (s, 9H); ES-LCMS m/z 263.0, 265.0 [M-t-Bu+H]⁺.

Step 4: 3-Bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a mixture of tert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (210mg, 636.20 μmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol,2 mL, 42.46 eq) at 25° C. The mixture was stirred at 25° C. for 0.5 h.TLC (PE/EtOAc=2/1, R_(f)=0.05) showed the starting material was consumedcompletely. The reaction mixture was concentrated under reduced pressureto yield 3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (210 mg,630.44 μmol, 99.1% yield, N/A purity, TFA) as a colorless gum, which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ ppm 4.77 (s, 1H), 3.56-3.38 (m, 4H), 3.30-3.20 (s, 1H),23.00-2.90 (m, 1H), 2.80-2.70 (m, 1H), 2.05-1.95 (s, 2H).

Step 5:(5S)-3-Bromo-5-[(3R)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazoleand(5R)-3-bromo-5-[(3R)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole

A mixture of 3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (210mg, 630.44 μmol, 1 eq, TFA), 1-(bromomethyl)-4-(trifluoromethyl)benzene(155 mg, 648.45 μmol, 1.03 eq) and DIEA (407.40 mg, 3.15 mmol, 549.05μL, 5 eq) in DCM (15 mL) was stirred at 25° C. for 12 h. The mixture wasconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 1/1,TLC: PE/EtOAc=1/1, R_(f)=0.25). The desired compound was concentratedunder reduced pressure to yield a residue (98 mg) which was separated bychiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobilephase: [0.1% NH₃.H₂O/EtOH]; B %: 15%-15%) to yield peak 1 and peak 2.Peak 1 was concentrated under reduced pressure to yield a residue whichwas dissolved in MeCN (10 mL) and water (10 mL) and lyophilized to yield(5S)-3-bromo-5-[(3R)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(44.31 mg, 117.47 μmol, 18.6% yield, 100.0% purity, SFC: R_(t)=2.488,Dr=96.54%, [α]^(29.3) _(D)=−63.16 (CHCl₃, c=0.057 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.58 (d, J=7.9 Hz, 2H), 7.45 (d,J=7.9 Hz, 2H), 4.68 (ddd, J=6.5, 8.9, 10.5 Hz, 1H), 3.77-3.60 (m, 2H),3.29-3.16 (m, 1H), 3.13-3.03 (m, 1H), 2.75-2.66 (m, 1H), 2.65-2.50 (m,3H), 2.40 (dd, J=5.0, 8.8 Hz, 1H), 2.12-2.01 (m, 1H), 1.68 (dd, J=6.4,13.4 Hz, 1H); ES-LCMS m/z 377.0, 379.0 [M+H]⁺. Peak 2 was concentratedunder reduced pressure to yield a residue which was dissolved in MeCN(10 mL) and water (10 mL) and lyophilized to yield(5R)-3-bromo-5-[(3R)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(39.56 mg, 102.47 μmol, 16.3% yield, 97.7% purity, SFC: R_(t)=2.631,Dr=99.62%, [α]^(29.2) _(D)=+53.85 (CHCl₃, c=0.052 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.59 (d, J=8.1 Hz, 2H), 7.46 (d,J=7.5 Hz, 2H), 4.72-4.64 (m, 1H), 3.75-3.65 (m, 2H), 3.27 (dd, J=10.4,17.2 Hz, 1H), 2.94 (dd, J=8.4, 17.2 Hz, 1H), 2.76-2.48 (m, 5H),2.09-1.98 (m, 1H), 1.60-1.50 (m, 1H); ES-LCMS m z 377.1, 379.1 [M+H]⁺.

I-59

Step 1: tert-Butyl4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate

A mixture of tert-butyl 4-aminopiperidine-1-carboxylate (500 mg, 2.50mmol, 1 eq), [4-(trifluoromethyl)phenyl]boronic acid (950 mg, 5.00 mmol,2 eq), Cu(OAc)₂ (900 mg, 4.96 mmol, 1.98 eq) and DIEA (1.6 g, 12.38mmol, 2.16 mL, 4.96 eq) in DCM (5 mL) was degassed and purged with O₂for 3 times and then the mixture was stirred under O₂ atmosphere at 28°C. for 12 h. TLC (PE/EtOAc=5/1, R_(f)=0.50) indicated Reactant 1 wasconsumed and two new spots formed. The reaction mixture was filtered andthe filtrate was concentrated under reduced pressure. The residue wasdiluted with water (20 mL) and extracted with EtOAc (25 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield the residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 1/1,TLC: PE/EtOAc=5/1, R_(f)=0.50) to yield tert-butyl4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate (300 mg, 609.81μmol, 24.4% yield, 70.0% purity) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.32 (d, J=8.6 Hz, 2H), 6.65 (d, J=8.6 Hz, 2H), 6.23(d, J=7.8 Hz, 1H), 3.84 (d, J=13.2 Hz, 2H), 3.51-3.39 (m, 1H), 2.88 (brs, 2H), 1.89-1.79 (m, 2H), 1.37 (s, 9H), 1.20 (d, J=7.8 Hz, 2H); ES-LCMSm/z 345.2 [M+H]⁺.

Step 2: N-[4-(Trifluoromethyl)phenyl]piperidin-4-amine

A solution of tert-butyl4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate (300 mg, 609.81μmol, 1 eq) in DCM (3 mL) and TFA (1 mL) was stirred at 28° C. for 1 h.The reaction mixture was diluted with water (10 mL), neutralized withNaHCO₃ until pH=7, and extracted with EtOAc (10 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield N-[4-(trifluoromethyl)phenyl]piperidin-4-amine(190 mg, 591.18 μmol, 97.0% yield, 76.0% purity) as a light yellow oil,which was used in the next step without further purification. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.34 (br s, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.68(d, J=8.6 Hz, 2H), 6.40 (d, J=7.8 Hz, 1H), 3.69-3.45 (m, 1H), 2.97 (t,J=11.0 Hz, 2H), 2.00 (d, J=11.2 Hz, 2H), 1.61-1.42 (m, 2H), 1.18 (d,J=17.1 Hz, 2H); ES-LCMS m/z 245.2 [M+H]⁺.

Step 3: 1-[4-[4-(Trifluoromethyl)anilino]-1-piperidyl]prop-2-en-1-one

To a solution of N-[4-(trifluoromethyl)phenyl]piperidin-4-amine (190 mg,591.18 μmol, 1 eq) and DIEA (230 mg, 1.78 mmol, 309.97 μL, 3.01 eq) inDCM (5 mL) was added dropwise prop-2-enoyl chloride (60 mg, 662.92 μmol,54.05 μL, 1.12 eq) at 0° C. The mixture was stirred at 28° C. for 12 h.The mixture was diluted with water (20 mL) and extracted with EtOAc (20mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield the residue which waspurified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 33%-63%, 10 min) toyield 1-[4-[4-(trifluoromethyl)anilino]-1-piperidyl]prop-2-en-1-one(15.98 mg, 52.60 μmol, 8.9% yield, 98.2% purity) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.37 (d, J=8.5 Hz, 2H), 6.84 (dd, J=10.5,16.6 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 6.31 (d, J=8.1 Hz, 1H), 6.11 (dd,J=1.9, 16.7 Hz, 1H), 5.68 (dd, J=1.9, 10.5 Hz, 1H), 4.30 (d, J=13.7 Hz,1H), 4.02 (d, J=13.1 Hz, 1H), 3.70-3.51 (m, 1H), 3.25 (t, J=12.0 Hz,1H), 2.92 (t, J=11.8 Hz, 1H), 1.89-2.00 (m, 2H), 1.37-1.18 (m, 2H);ES-LCMS m/z 299.2 [M+H]⁺.

I-149

Step 1: tert-Butyl3-bromo-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate

A mixture of tert-butyl 4-methylenepiperidine-1-carboxylate (500 mg,2.53 mmol, 1 eq), dibromomethanone oxime (616.91 mg, 3.04 mmol, 1.2 eq),NaHCO₃ (212.92 mg, 2.53 mmol, 1 eq) in EtOAc (10 mL) was degassed andpurged with N₂ for 3 times and then the mixture was stirred under N₂atmosphere at 25° C. for 16 h. The mixture was diluted with water (20mL) and extracted with EtOAc (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedto yield tert-butyl3-bromo-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (530 mg, 1.58mmol, 62.2% yield, 95.0% purity) as yellow oil, which was used in thenext step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.43-3.39 (m, 4H), 3.14 (s, 2H), 1.69-1.66 (m, 4H), 1.38 (s, 9H);ES-LCMS m/z: 262.9, 264.9 [M-t-Bu+H]⁺.

Step 2: 3-Bromo-1-oxa-2,8-diazaspiro[4.5]dec-2-ene

A mixture of tert-butyl3-bromo-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (530 mg, 1.58mmol, 1 eq), TFA (179.86 mg, 1.58 mmol, 116.79 μL, 1 eq) in DCM (5 mL)was degassed and purged with N₂ for 3 times and then the mixture wasstirred under N₂ atmosphere at 25° C. for 2 h. The reaction mixture wasconcentrated to yield 3-bromo-1-oxa-2, 8-diazaspiro[4.5]dec-2-ene (300mg, 1.10 mmol, 69.5% yield, 80.0% purity) as yellow oil which was usedin the next step without further purification. ES-LCMS m/z: 219.1,221.1[M+H]⁺.

Step 3:3-Bromo-8-[[4-(trifluoromethyl)phenyl]methyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene

A mixture of 3-bromo-1-oxa-2,8-diazaspiro[4.5]dec-2-ene (150 mg, 547.75μmol, 1 eq), 1-(bromomethyl)-4-(trifluoromethyl)benzene (130.93 mg,547.75 μmol, 10.56 μL, 1 eq) and DIEA (283.17 mg, 2.19 mmol, 381.63 μL,4 eq) in DCM (5 mL) was degassed and purged with N₂ for 3 times and thenthe mixture was stirred under N₂ atmosphere at 25° C. for 12 h. TLC(PE/EtOAc=1/1, R_(f)=0.52) showed the staring material was consumedcompletely and one new spot was formed. The reaction mixture wasconcentrated to give a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water 0.05%NH₃.H₂O+10 mM NH₄HCO₃)—CAN]; B %: 52%-67%, 14 min) and then bypreparative TLC (SiO₂—, PE/EtOAc=1/1, R_(f)=0.52) to yield3-bromo-8-[[4-(trifluoromethyl)phenyl]methyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene(24.99 mg, 66.25 μmol, 12.1% yield, 100.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.57 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz,2H), 3.57 (s, 2H), 2.95 (s, 2H), 2.57-2.48 (m, 4H), 1.98-1.95 (m, 2H),1.83-1.79 (m, 2H); ES-LCMS m/z: 377.1, 379.1 [M+H]⁺.

I-60

Step 1:1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-ol

To a solution of 1,2,3,4-tetrahydroquinolin-3-ol (500 mg, 3.35 mmol, 1eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (3.20 g, 13.41 mmol,2.04 mL, 4 eq) in THE (20 mL) was added TEA (3.39 g, 33.51 mmol, 4.66mL, 10 eq). The mixture was stirred at 25° C. for 12 h. TLC(PE/EtOAc=3/1, R_(f)=0.65) indicated about half of the starting materialwas remained and one new spot formed. The reaction mixture wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.65)to yield1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-ol (200mg, 618.27 μmol, 18.4% yield, 95.0% purity) as yellow oil. ¹H NMR (500MHz, CDCl₃) δ ppm 7.83-7.64 (m, 4H), 7.33-7.27 (m, 2H), 6.94 (dt, J=0.6,7.3 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 4.88-4.74 (m, 2H), 4.64-4.51 (m,1H), 3.80-3.70 (m, 1H), 3.55 (ddd, J=1.8, 5.4, 11.5 Hz, 1H), 3.38 (dd,J=3.8, 16.0 Hz, 1H), 3.12 (dd, J=4.4, 16.0 Hz, 1H).

Step 2:[1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]methanesulfonate

To a solution of1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-ol (200mg, 618.27 μmol, 1 eq) and TEA (312.81 mg, 3.09 mmol, 430.28 μL, 5 eq)in THF (6 mL) was added MsCl (170 mg, 1.48 mmol, 114.86 μL, 2.40 eq)under N₂. The mixture was stirred at 30° C. for 2 h. The reactionmixture was quenched by addition of water (50 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toyield[1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]methanesulfonate(170 mg, crude) as a yellow solid, which was used in the next stepwithout further purification. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.60-7.42(m, 4H), 7.09-7.00 (m, 2H), 6.71 (t, J=7.3 Hz, 1H), 6.52 (d, J=8.2 Hz,1H), 5.40-5.23 (m, 1H), 4.71-4.43 (m, 2H), 3.69-3.63 (m, 1H), 3.61-3.55(m, 1H), 3.31-3.24 (m, 1H), 3.19-3.12 (m, 1H), 3.03 (s, 3H); ES-LCMS m/z386.0 [M+H]⁺.

Step 3:3-Azido-1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline

To a solution of[1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]methanesulfonate(170 mg, 441.10 μmol, 1 eq) in DMF (3 mL) was added NaN₃ (86.03 mg, 1.32mmol, 3 eq) under N₂. The mixture was stirred at 80° C. for 1 h. Thereaction mixture was quenched by addition of sat. aq. NaHCO₃ (20 mL),extracted with DCM (30 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to removeabout 80 mL DCM, and then THE (30 mL) was added to the above solution.The solution was concentrated (until about 3 mL THE remained) to yield3-azido-1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline(146 mg, 439.33 μmol, 99.6% yield, N/A purity) in THE (3 mL) as a brownliquid, which was used in next step directly without furtherpurification. ES-LCMS m/z 333.0 [M+H]⁺.

Step 4:1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-amine

To a solution of3-azido-1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline(146 mg, 439.33 μmol, 1 eq) in THE (3 mL) and H₂O (0.3 mL) was addedPPh₃ (230.46 mg, 878.66 μmol, 2 eq). The mixture was stirred at 25° C.for 12 h. The reaction mixture was concentrated. The residue waspurified by flash silica gel chromatography (from DCM/MeOH=1/0 to 10/1,TLC: DCM/MeOH=10/1, R_(f)=0.27) to yield1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-amine(80 mg, 247.58 μmol, 56.3% yield, 94.8% purity) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.53-7.42 (m, 4H), 7.03 (d, J=7.0 Hz, 2H),6.69-6.62 (m, 1H), 6.51 (d, J=7.8 Hz, 1H), 4.63-4.46 (m, 2H), 3.75 (t,J=6.7 Hz, 1H), 3.51-3.40 (m, 2H), 3.09 (d, J=17.2 Hz, 1H), 2.69 (dd,J=7.2, 15.5 Hz, 1H); ES-LCMS m/z 307.1 [M+H]⁺.

Step 5:N-[(3S)-1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]prop-2-enamide

To a solution of1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-amine(80 mg, 247.58 μmol, 1 eq) in THE (5 mL) was added TEA (75.16 mg, 742.74μmol, 103.38 μL, 3 eq) and prop-2-enoyl chloride (44.82 mg, 495.16 μmol,40.37 μL, 2 eq). The mixture was stirred at 25° C. for 1 h. The reactionmixture was concentrated. The residue was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=1/1, R_(f)=0.52)to yield a product, which was separated by SFC (column: DAICEL CHIRALPAKAD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B %:20%-20%, min) to yield peak 1 (2.919) and peak 2 (3.182). Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (10 mL) and lyophilized to yieldN-[(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]prop-2-enamide(19.79 mg, 54.53 μmol, 22.0% yield, 99.3% purity) (SFC: R_(t)=3.260,ee=100%, [α]^(28.3) _(D)=−80.702 (MeOH, c=0.057 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59-7.46 (m, 2H), 7.43 (d, J=5.1Hz, 2H), 7.12-7.00 (m, 2H), 6.71 (t, J=7.0 Hz, 1H), 6.57 (d, J=8.2 Hz,1H), 6.28 (dd, J=1.2, 16.8 Hz, 1H), 6.12-5.97 (m, 1H), 5.84 (d, J=8.2Hz, 1H), 5.64 (dd, J=1.2, 10.2 Hz, 1H), 4.70-4.60 (m, 1H), 4.59-4.46 (m,2H), 3.59 (d, J=11.3 Hz, 1H), 3.43-3.32 (m, 1H), 3.22 (dd, J=4.5, 16.2Hz, 1H), 2.82 (d, J=16.4 Hz, 1H); ES-LCMS m/z 361.2 [M+H]⁺.

I-119 & I-120

Step 1: 4-Bromo-2-methoxy-6-nitro-phenol

To a solution of 4-bromo-2-methoxy-phenol (5 g, 24.63 mmol, 1 eq) inAcOH (75 mL) was added HNO₃ (2.74 g, 29.55 mmol, 68 purity, 1.2 eq) withstirred at 0° C. under N₂. The mixture was allowed to warm to roomtemperature (25° C.) with stirred for 1 h under N₂. TLC (PE/EtOAc=4/1,R_(f)=0.6) showed that new point was formed and start material wasconsumed completely. The mixture was poured into ice water (150 mL) withstirred at 0° C. for 15 m. The mixture was extracted with EtOAc (150mL×3). The combined organic layer was dried over Na₂SO₄, filtrated andconcentrated to yield 4-bromo-2-methoxy-6-nitro-phenol (6.1 g, 22.13mmol, 89.9% yield, 90.0% purity) as a white solid, which was used in thenext step without further purification. ES-LCMS m/z no desired MS found.

Step 2: (4-Bromo-2-methoxy-6-nitro-phenyl) 4-methylbezenesulfonate

To a solution of 4-bromo-2-methoxy-6-nitro-phenol (6.1 g, 22.13 mmol, 1eq) in DCM (10 mL) was added pyridine (35.87 g, 453.45 mmol, 36.60 mL,20.49 eq) and 4-methylbenzenesulfonyl chloride (10.55 g, 44.27 mmol, 2.0eq). The mixture was stirred at 25° C. for 15 h. TLC (PE/EtOAc=4/1,R_(f)=0.4) indicated start material was consumed completely and one newspot formed. The reaction mixture was quenched by addition of H₂O (20mL) at 25° C. and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=10/1, TLC:PE/EtOAc=4/1, R_(f)=0.4) to yield (4-bromo-2-methoxy-6-nitro-phenyl)4-methylbenzenesulfonate (1.48 g, 3.50 mmol, 15.8% yield, 95.0% purity)as a white solid.

Step 3: 4-Bromo-2-methoxy-6-nitro-benzenethiol

To a solution of (4-bromo-2-methoxy-6-nitro-phenyl)4-methylbenzenesulfonate (1.48 g, 3.50 mmol, 1 eq) in DMF (15 mL) wasadded Na₂S.9H₂0 (1.26 g, 5.24 mmol, 880.68 μL, 1.5 eq) with stirredunder N₂ atmosphere. The mixture was stirred under N₂ atmosphere at 28°C. for 15 h. TLC (PE/EtOAc=3/1, R_(f)=0.72) showed that new point wasformed and start material was consumed completely. The reaction mixturewas quenched by addition of H₂O (20 mL) and extracted with EtOAc (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield4-bromo-2-methoxy-6-nitro-benzenethiol (1.08 g, 3.48 mmol, 99.4% yield,85.0% purity) as a yellow solid, which was used in the next step withoutfurther purification.

Step 4: 5-Bromo-7-methoxy-1,3-benzothiazole

To a solution of 4-bromo-2-methoxy-6-nitro-benzenethiol (1.08 g, 3.48mmol, 1 eq) in HCOOH (20 mL) was added Zn (1.14 g, 17.38 mmol, 5 eq)with stirred under N₂ atmosphere. The mixture was stirred under N₂atmosphere at 110° C. for 15 h. TLC (PE/EtOAc=3/1, R_(f)=0.72) showedthat new point was formed and start material was consumed completely.The reaction mixture was quenched by addition of H₂O (20 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield 5-bromo-7-methoxy-1,3-benzothiazole (820 mg,3.19 mmol, 91.8% yield, 95.0% purity) as a black oil, which was used inthe next step without further purification.

Step 5: 5-Bromo-1,3-benzothiazol-7-ol

To a solution of 5-bromo-7-methoxy-1, 3-benzothiazole (820 mg, 3.19mmol, 1 eq) in DCM (15 mL) was added BBr₃ (799.46 mg, 3.19 mmol, 307.49μL, 1 eq) with stirred at −60° C. under N₂ atmosphere. The mixture wasstirred under N₂ atmosphere at 28° C. for 15 h. TLC (PE/EtOAc=3/1,R_(f)=0.47) showed that new point was formed and start material wasconsumed completely. The reaction mixture was poured into ice water (20mL) and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue which was purified bypreparative TLC (PE/EtOAc=2/1, TLC: PE/EtOAc=3/1, R_(f)=0.47) to yield5-bromo-1,3-benzothiazol-7-ol (258 mg, 1.12 mmol, 35.1% yield, 100.0%purity) as a black solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (s, 1H),7.69 (d, J=1.6 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H); ES-LCMS m/z 231.7[M+H]⁺.

Step 6: 5-Vinyl-1,3-benzothiazol-7-ol

To a solution of 5-bromo-1,3-benzothiazol-7-ol (258 mg, 1.12 mmol, 1 eq)and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (259.05 mg, 1.68mmol, 285.30 μL, 1.5 eq) in 1,4-dioxane (2 mL) and H₂O (0.5 mL) wasadded Pd(dppf)Cl₂ (82.05 mg, 112.13 μmol, 0.1 eq) and Cs₂CO₃ (548.03 mg,1.68 mmol, 1.5 eq) with stirred at 35° C. under N₂ atmosphere. Themixture was stirred under N₂ atmosphere at 110° C. for 10 h. TLC(PE/EtOAc=3/1, R_(f)=0.5) showed that new point was formed and startmaterial was consumed completely. The reaction mixture was quenched byaddition of H₂O (20 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue whichwas purified by preparative TLC (PE/EtOAc=3/1, TLC (PE/EtOAc=3/1,R_(f)=0.5)) to yield 5-vinyl-1, 3-benzothiazol-7-ol (180 mg, 812.54μmol, 72.5% yield, 80.0% purity) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.64 (s, 1H), 9.36-9.28 (m, 1H), 7.66 (s, 1H), 7.01 (s,1H), 6.83 (dd, J=11.5, 17.5 Hz, 1H), 5.84 (d, J=17.5 Hz, 1H), 5.31 (d,J=11.0 Hz, 1H).

Step 7: 7-[3-(Trifluoromethyl)phenoxy]-5-vinyl-1,3-benzothiazole

To a solution of 5-vinyl-1,3-benzothiazol-7-ol (170 mg, 767.40 μmol, 1eq) and [3-(trifluoromethyl)phenyl]boronic acid (437.25 mg, 2.30 mmol,3.0 eq) in DCM (110 mL) was added Cu(OAc)₂ (278.77 mg, 1.53 mmol, 2 eq)and Et₃N (388.26 mg, 3.84 mmol, 534.06 μL, 5 eq). The mixture wasstirred under O₂ (15 Psi) at 35° C. for 10 h. TLC (PE/EtOAc=3/1,R_(f)=0.6) showed that new point was formed and start material wasconsumed completely. The reaction mixture was quenched by addition ofH₂O (20 mL) and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue which was purifiedby preparative TLC (PE/EtOAc=1/1, TLC: PE/EtOAc=3/1, R_(f)=0.6) to yield7-[3-(trifluoromethyl)phenoxy]-5-vinyl-1,3-benzothiazole (65 mg, 149.70μmol, 19.5% yield, 74.0% purity) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ ppm 9.05 (s, 1H), 7.98 (s, 1H), 7.53-7.48 (m, 1H), 7.36 (s,1H), 7.20 (d, J=7.5 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.82(dd, J=11.0, 17.0 Hz, 1H), 5.79 (d, J=17.5 Hz, 1H), 5.36 (d, J=11.0 Hz,1H); ES-LCMS m/z 321.9 [M+H]⁺.

Step 8:3-Bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazole

To a solution of7-[3-(trifluoromethyl)phenoxy]-5-vinyl-1,3-benzothiazole (55 mg, 126.67μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (106.41 mg, 1.27 mmol,49.27 μL, 10 eq) and dibromomethanone oxime (28.26 mg, 139.33 μmol, 1.1eq). The mixture was stirred at 30° C. for 10 h. TLC (PE/EtOAc=3/1,R_(f)=0.7) showed that new point was formed and start material wasconsumed completely. The reaction mixture was quenched by addition ofH₂O (5 mL) and extracted with EtOAc (10 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue which was purifiedby preparative TLC (PE/EtOAc=3/1, TLC: PE/EtOAc=3/1, R_(f)=0.70) toyield3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazole(58 mg, 123.00 μmol, 97.1% yield, 94.0% purity) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ ppm 9.04 (s, 1H), 7.93 (s, 1H), 7.56-7.43 (m, 2H),7.24-7.18 (m, 1H), 7.00 (s, 1H), 5.80 (dd, J=8.5, 10.5 Hz, 1H),3.74-3.64 (m, 1H), 3.26-3.19 (m, 1H); ES-LCMS m/z 443.0 [M+H]⁺.

Step 9:(5R)-3-Bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazole

3-Bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazole(58 mg, 123.00 μmol, 1 eq) was separated by SFC (column: REGIS (s,s)WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O/EtOH]; B %:35%-35%, min) to yield peak 1 and peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (15 mL)and water (15 mL) and lyophilized to yield(5R)-3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazole(17.89 mg, 38.74 μmol, 31.5% yield, 95.9% purity, SFC: R_(t)=3.100,ee=100%, [α]^(28.4) _(D)=−92.857 (MeOH, c=0.028 g/100 mL)) as colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.30 (s, 1H), 7.94 (s, 1H), 7.66-7.58(m, 1H), 7.55-7.49 (m, 1H), 7.40 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.09(s, 1H), 5.89-5.84 (m, 1H), 3.84-3.77 (m, 1H), 3.27-3.28 (m, 1H);ES-LCMS m/z 444.8 [M+H]*. Peak 2 was concentrated under reduced pressureto yield a residue which was dissolved in MeCN (15 mL) and water (15 mL)and lyophilized to yield(5S)-3-bromo-5-[7-[3-(trifluoromethyl)phenoxy]-1,3-benzothiazol-5-yl]-4,5-dihydroisoxazole(14.54 mg, 32.47 μmol, 26.4% yield, 98.9% purity, SFC: R_(t)=3.547,ee=100%, [α]^(28.4) _(D)=+92.308 (MeOH, c=0.026 g/100 mL)) as colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.30 (s, 1H), 7.94 (s, 1H), 7.66-7.58(m, 1H), 7.56-7.50 (m, 1H), 7.40 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.09(s, 1H), 5.89-5.84 (m, 1H), 3.84-3.76 (m, 1H), 3.28-3.25 (m, 1H);ES-LCMS m/z 442.9 [M+H]*.

I-61

Step 1: tert-Butyl N-(1-prop-2-enoyl-4-piperidyl)carbamate

To a solution of tert-butyl N-(4-piperidyl)carbamate (2 g, 9.99 mmol, 1eq) in DCM (25 mL) was added DIEA (1.29 g, 9.99 mmol, 1.74 mL, 1 eq) andprop-2-enoyl chloride (1.08 g, 11.98 mmol, 977.11 μL, 1.2 eq). Themixture was stirred at 25° C. for 1 h under N₂ atmosphere. The reactionmixture was diluted with water (50 mL) then extracted with EtOAc (30mL×3). The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated to yield a residue which was purified byflash silica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=1/1, R_(f)=0.30) to yield tert-butylN-(1-prop-2-enoyl-4-piperidyl)carbamate (1.65 g, 6.40 mmol, 64.1% yield,98.7% purity) as a light yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm6.86 d, J=7.8 Hz, 1H), 6.79 (dd, J=10.5, 16.6 Hz, 1H), 6.07 (dd, J=2.4,16.6 Hz, 1H), 5.64 (dd, J=2.4, 10.5 Hz, 1H), 4.25 (d, J=12.8 Hz, 1H),3.95 (d, J=13.4 Hz, 1H), 3.49 (d, J=7.5 Hz, 1H), 3.17-3.02 (m, 1H), 2.75(t, J=11.7 Hz, 1H), 1.75-1.73 (m, 2H), 1.38 (s, 9H), 1.27-1.17 (m, 2H);ES-LCMS m/z 255.2 [M+H]⁺.

Step 2: 1-(4-Amino-1-piperidyl)prop-2-en-1-one

To a solution of tert-butyl N-(1-prop-2-enoyl-4-piperidyl)carbamate (300mg, 1.16 mmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol, 2mL, 23.20 eq). The mixture was stirred at 25° C. for 1 h under N₂atmosphere. The reaction mixture was concentrated to yield1-(4-amino-1-piperidyl)prop-2-en-1-one (300 mg, 1.06 mmol, 91.3% yield,95.0% purity, TFA) as yellow oil which was used in the next step withoutfurther purification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.93 (s, 2H), 6.81(dd, J=10.5, 16.6 Hz, 1H), 6.10 (dd, J=2.3, 16.8 Hz, 1H), 5.69 (dd,J=2.3, 10.5 Hz, 1H), 4.41 (d, J=12.1 Hz, 1H), 4.08 (d, J=13.3 Hz, 1H),3.28 (dt, J=5.4, 10.5 Hz, 1H), 3.10 (t, J=12.8 Hz, 1H), 2.74-2.62 (m,1H), 1.92 (d, J=11.7 Hz, 2H), 1.35 (t, J=12.5 Hz, 2H).

Step 3: Ethyl3-[[3-(4-isopropylthiazole-2-carbonyl)-1H-indol-6-yl]oxy]propanoate

To a solution of(6-hydroxy-1H-indol-3-yl)-(4-isopropylthiazol-2-yl)methanone (120 mg,387.64 μmol, 1 eq) and ethyl 3-bromopropanoate (84.21 mg, 465.17 μmol,1.2 eq) in DMF (5 mL) was added Cs₂CO₃ (378.90 mg, 1.16 mmol, 3 eq). Themixture was stirred at 55° C. for 6 h under N₂ atmosphere. The reactionmixture was diluted with water (50 mL) then extracted with EtOAc (30mL×3). The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated to yield a residue which was purified byflash silica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=1/1, R_(f)=0.55) to yield ethyl3-[[3-(4-isopropylthiazole-2-carbonyl)-1H-indol-6-yl]oxy]propanoate (160mg, 252.96 μmol, 65.3% yield, 61.1% purity) as brown oil. ¹H NMR (500MHz, DMSO-d₆) δ ppm 7.71 (s, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.59-7.51 (m,2H), 6.80 (dd, J=10.5, 16.6 Hz, 1H), 6.06 (dd, J=2.4, 16.7 Hz, 1H), 5.64(dd, J=2.4, 10.5 Hz, 1H), 4.18 (d, J=12.4 Hz, 1H), 3.93 (d, J=13.9 Hz,1H), 3.81 (s, 2H), 3.10 (t, J=11.4 Hz, 1H), 2.81 (t, J=11.0 Hz, 1H),2.64-2.61 (m, 1H), 2.45 (s, 1H), 1.85-1.83 (m, 2H), 1.22-1.14 (m, 2H);ES-LCMS m/z 313.2 [M+H]⁺.

I-43

Step 1: 6-(Trifluoromethyl)quinoline

To a stirred solution of 4-(trifluoromethyl)aniline (2 g, 12.41 mmol,1.54 mL, 1 eq) in sulfuric acid (55.20 g, 422.10 mmol, 30 mL, 75%purity, 34.01 eq) was added nitrobenzene (1.53 g, 12.41 mmol, 1.27 mL, 1eq) and glycerol (2.86 g, 31.03 mmol, 2.32 mL, 2.5 eq). The reactionmixture was stirred at 150° C. for 3 h. The reaction mixture was pouredinto ice-water (200 mL) then stirred at 28° C. for 1 h. The mixture wasfiltered and the filtrate was extracted with EtOAc (100 mL×5). Thecombined organic layers were washed with saturated NaCl solution (100mL×2), dried over Na₂SO₄, filtered and the filtrate was concentrated toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.25) to yield6-(trifluoromethyl)quinoline (1.8 g, 9.13 mmol, 73.5% yield, 100.0%purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.05 (dd, J=1.7,4.2 Hz, 1H), 8.26 (dd, J=8.6, 13.7 Hz, 2H), 8.17 (s, 1H), 7.91 (dd,J=1.8, 8.9 Hz, 1H), 7.53 (dd, J=4.2, 8.3 Hz, 1H).

Step 2: 6-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline

To a stirred solution of 6-(trifluoromethyl)quinoline (1.1 g, 5.54 mmol,1 eq) in MeOH (10 mL) was added PtO₂ (100 mg, 440.37 μmol) slowly. Thereaction mixture was stirred at 28° C. for 12 h under H₂ atmosphere (50psi). TLC (PE/EtOAc=1/1, R_(f)=0.30) showed the starting material wasconsumed completely and one new spot was detected. The reaction mixturewas filtered through a pad of celite. The filtrate was concentratedunder reduced pressure to yield6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (800 mg, 3.78 mmol,68.2% yield, 95.0% purity) as yellow oil which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.22-7.15(m, 2H), 6.45 (d, J=9.0 Hz, 1H), 4.16 (s, 1H), 3.37-3.33 (m, 2H), 2.78(t, J=6.4 Hz, 2H), 1.98-1.92 (m, 2H).

Step 3: N-(3-Bromophenyl)prop-2-enamide

To a stirred solution of 3-bromoaniline (2 g, 11.63 mmol, 1.27 mL, 1 eq)in DCM (20 mL) was added DIEA (4.51 g, 34.88 mmol, 6.08 mL, 3 eq) andprop-2-enoyl chloride (1.05 g, 11.63 mmol, 948.00 μL, 1 eq). Thereaction mixture was stirred at 29° C. for 1 h. TLC (PE/EtOAc=3/1,R_(f)=0.30) showed the starting material was consumed completely and onenew spot was detected. The reaction mixture was concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.3) to yield N-(3-bromophenyl)prop-2-enamide (2.3 g, 10.17 mmol,87.5% yield, 100.0% purity) as white solid. ¹H NMR (500 MHz, DMSO-d₆) δppm 10.43-10.20 (m, 1H), 8.03 (t, J=1.8 Hz, 1H), 7.55 (td, J=1.6, 7.8Hz, 1H), 7.38-7.19 (m, 2H), 6.48-6.35 (m, 1H), 6.33-6.23 (m, 1H), 5.79(dd, J=2.0, 10.1 Hz, 1H); ES-LCMS m/z 226.0, 228.0 [M+H]⁺.

Step 4: N-[4-[4-(Trifluoromethyl)anilino]cyclohexyl]prop-2-enamide

To a solution of 6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (300mg, 1.42 mmol, 1 eq) in 1,4-dioxane (9 mL) was added Pd₂(dba)₃ (129.72mg, 141.66 μmol, 0.1 eq), RuPhos (66.10 mg, 141.66 μmol, 0.1 eq),t-BuONa (272.28 mg, 2.83 mmol, 2 eq) and N-(3-bromophenyl)prop-2-enamide(500 mg, 2.21 mmol, 1.56 eq). The mixture was bubbled with N₂ for 3 minand stirred at 120° C. for 2 h under microwave. The reaction mixture wasfiltered through a pad of celite. The filtrate was concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1,R_(f)=0.55) then re-purified by preparative HPLC (column: PhenomenexSynergi C18 150*30 mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %:67%-87%, 10 min). The desired fraction was lyophilized to yield thedesired product (HCl salt) which was added to saturated NaHCO₃ solution(10 mL) then extracted with EtOAc (10 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated thenlyophilized to yieldN-[3-[6-(trifluoromethyl)-3,4,4a,8a-tetrahydro-2H-quinolin-1-yl]phenyl]prop-2-enamide(25 mg, 71.76 μmol, 5.1% yield, 100.0% purity) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.23 (s, 1H), 7.68 (s, 1H), 7.49 (d, J=8.1 Hz,1H), 7.39 (t, J=8.1 Hz, 1H), 7.32 (s, 1H), 7.18 (d, J=8.8 Hz, 1H),7.03-6.97 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.48-6.36 (m, 1H), 6.29-6.19(m, 1H), 5.75 (dd, J=2.0, 10.0 Hz, 1H), 3.66-3.55 (m, 2H), 2.86 (t,J=6.2 Hz, 2H), 2.05-1.94 (m, 2H); ES-LCMS m/z 347.1 [M+H]⁺.

I-121 & I-122

Step 1:N-[2-[[(5S)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazol-3-yl]sulfanyl]ethyl]acetamide&N-[2-[[(5R)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazol-3-yl]sulfanyl]ethyl]acetamide

To a solution of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(500 mg, 1.12 mmol, 1 eq), N-(2-sulfanylethyl)acetamide (266.97 mg, 2.24mmol, 238.37 μL, 2 eq) in THE (10 mL) was added LiHMDS (1 M, 3.36 mL, 3eq). The mixture was stirred at 25° C. for 12 h. The reaction mixturewas quenched by addition of water (50 mL), extracted with EtOAc (30mL×3). The organic layer was washed with brine (20 mL), dried overNa₂SO₄, filtered, concentrated to yield a residue which was purified bypreparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobilephase: [water (0.05% HCl)-ACN]; B %: 58%-78%, 10 min), followed bylyophilization to yield product which was separated by SFC (column:DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃.H₂OETOH]; B %: 20%-20%, min) to yield Peak 1: R_(t)=3.414 and Peak 2:R_(t)=3.780. Peak 1 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (20 mL) and H₂O (10 mL) andlyophilized to yieldN-[2-[[(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazol-3-yl]sulfanyl]ethyl]acetamide(15.32 mg, 34.94 μmol, 3.1% yield, 100% purity SFC: R_(t)=3.406,ee=100%, [α]^(26.2) _(D)=−56 (MeOH, c=0.05 g/100 mL)) as a white solid.¹H NMR (500 MHz, CDCl₃) δ ppm 7.43-7.39 (m, 1H), 7.31 (t, J=7.7 Hz, 2H),7.15 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.93 (s,1H), 6.05 (s, 1H), 5.63-5.50 (m, 1H), 3.60 (q, J 6.1 Hz, 2H), 3.44 (dd,J=10.3, 16.4 Hz, 1H), 3.20 (t, J=6.3 Hz, 2H), 3.02 (dd, J=8.3, 16.4 Hz,1H), 2.22 (s, 3H), 1.98 (s, 3H); ES-LCMS m/z 439.2 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (10 mL) and lyophilized to yieldN-[2-[[(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazol-3-yl]sulfanyl]ethyl]acetamide(15.89 mg, 35.50 μmol, 3.1% yield, 97.9% purity SFC: R_(t)=3.777,ee=99.0%, [α]^(26.2) _(D)=+44.9 (MeOH, c=0.049 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.44-7.39 (m, 1H), 7.33-7.28 (m,2H), 7.16-7.09 (m, 2H), 7.03 (d, J=8.2 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H),6.12-5.98 (m, 1H), 5.60-5.52 (m, 1H), 3.60 (q, J 6.3 Hz, 2H), 3.44 (dd,J=10.6, 16.4 Hz, 1H), 3.20 (t, J=6.3 Hz, 2H), 3.02 (dd, J=8.2, 16.4 Hz,1H), 2.22 (s, 3H), 1.98 (s, 3H); ES-LCMS m/z 439.2 [M+H]⁺.

I-62 & I-63

Step 1: 1-[4-(Trifluoromethyl)phenyl]ethyl methanesulfonate

To a solution of 1-[4-(trifluoromethyl)phenyl]ethanol (500 mg, 2.63mmol, 1 eq) and DIEA (680 mg, 5.26 mmol, 916.44 μL, 2 eq) in DCM (10 mL)was added MsCl (325 mg, 2.84 mmol, 219.59 μL, 1.08 eq) at 0° C. Themixture was stirred at 0° C. for 1 h. The reaction mixture was dilutedwith H₂O (30 mL) and extracted with EtOAc (30 mL×3). The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressureto yield 1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate (700 mg,2.61 mmol, 99.2% yield, N/A purity) as a brown gum, which was used inthe next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 7.68 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 5.80 (q, J=6.7 Hz,1H), 2.86 (s, 3H), 1.74 (d, J=6.7 Hz, 3H).

Step 2:N-[1-[(1R)-1-[4-(Trifluoromethyl)phenyl]ethyl]-4-piperidyl]prop-2-enamideandN-[1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]prop-2-enamide

A mixture of 1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate (400mg, 1.49 mmol, 1 eq), N-(4-piperidyl)prop-2-enamide (450 mg, 1.65 mmol,1.11 eq, HCl) and Cs₂CO₃ (2.43 g, 7.46 mmol, 5 eq) in DMF (20 mL) wasstirred at 25° C. for 12 h. The reaction mixture was diluted with H₂O(80 mL) and extracted with EtOAc (100 mL×3). The organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by preparative HPLC (column: PhenomenexSynergi C18 150*30 mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %:20%-40%, 9 min). The desired fraction was basified with saturatedaqueous NaHCO₃ until pH=8 and extracted with EtOAc (150 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue (98 mg) which was separated bychiral SFC (column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); mobilephase: [0.1% NH₃H₂O/EtOH]; B %: 15%-15%) to yield peak 1 and peak 2.Peak 1 was concentrated under reduced pressure to yield a residue whichwas dissolved in MeCN (20 mL) and water (20 mL) and lyophilized to yieldN-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]prop-2-enamide(30.98 mg, 94.93 μmol, 6.4% yield, 100.0% purity, SFC: R_(t)=1.728,ee=100.00%, [α]^(26.5) _(D)=+22.22 (CHCl₃, c=0.054 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.57 (d, J=8.1 Hz, 2H), 7.44 (d,J=8.1 Hz, 2H), 6.27 (d, J=16.9 Hz, 1H), 6.06 (dd, J=10.2, 16.9 Hz, 1H),5.64 (d, J=10.2 Hz, 1H), 5.46-5.36 (m, 1H), 3.93-3.80 (m, 1H), 3.52-3.42(m, 1H), 2.98 (d, J=10.5 Hz, 1H), 2.70 (d, J=11.1 Hz, 1H), 2.20-2.06 (m,2H), 2.00 (d, J=14.6 Hz, 1H), 1.89 (d, J=12.4 Hz, 1H), 1.54-1.38 (m,2H), 1.35 (d, J=6.7 Hz, 3H); ES-LCMS m/z 327.2 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and water (20 mL) and lyophilized to yieldN-[1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]prop-2-enamide(34.99 mg, 107.21 μmol, 7.2% yield, 100.0% purity, SFC: R_(t)=2.038,ee=99.40%, [α]^(26.5) _(D)=−32.14 (CHCl₃, c=0.056 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.58 (d, J=8.1 Hz, 2H), 7.44 (d,J=8.1 Hz, 2H), 6.27 (dd, J=1.1, 16.9 Hz, 1H), 6.06 (dd, J=10.2, 16.9 Hz,1H), 5.64 (dd, J=0.8, 10.4 Hz, 1H), 5.46-5.36 (m, 1H), 3.93-3.81 (m,1H), 3.48 (d, J=6.4 Hz, 1H), 2.99 (d, J=8.9 Hz, 1H), 2.71 (d, J=10.5 Hz,1H), 2.19-2.06 (m, 2H), 2.00 (d, J=13.1 Hz, 1H), 1.90 (d, J=12.5 Hz,1H), 1.55-1.41 (m, 2H), 1.36 (d, J=6.6 Hz, 3H); ES-LCMS m z 327.2[M+H]⁺.

I-63

Step 1: [(1R)-1-[4-(Trifluoromethyl)phenyl]ethyl]methanesulfonate

To a solution of (1R)-1-[4-(trifluoromethyl)phenyl]ethanol (200 mg, 1.05mmol, 1 eq) and DIEA (410 mg, 3.17 mmol, 552.56 μL, 3.02 eq) in DCM (10mL) was added MsCl (130 mg, 1.13 mmol, 87.84 μL, 1.08 eq) at 0° C. Themixture was stirred at 25° C. for 1 h. The reaction mixture was quenchedwith H₂O (20 mL) and extracted with DCM (20 mL×3). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toyield [(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]methanesulfonate (280 mg,1.04 mmol, 99.2% yield, N/A purity) as a brown gum, which was used inthe next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 7.67 (d, J=7.8 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 5.78 (q, J=6.7 Hz,1H), 2.85 (s, 3H), 1.72 (d, J=6.3 Hz, 3H).

Step 2:N-[1-[(1S)-1-[4-(Trifluoromethyl)phenyl]ethyl]-4-piperidyl]prop-2-enamide

A mixture of [(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]methanesulfonate(280 mg, 1.04 mmol, 1 eq), N-(4-piperidyl)prop-2-enamide (300 mg, 1.10mmol, 1.06 eq, HCl) and Cs₂CO₃ (1.3 g, 3.99 mmol, 3.82 eq) in DMF (10mL) was stirred at 25° C. for 48 h. The reaction mixture was dilutedwith H₂O (50 mL) and extracted with EtOAc (50 mL×3). The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressureto yield a residue which was purified by preparative HPLC (column:Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water (0.05%HCl)-ACN]; B %: 14%-34%, 10 min). The desired fraction was basified withsaturated aqueous NaHCO₃ until pH=8 and extracted with EtOAc (150 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue (85 mg with 90.92% ee value) whichwas separated by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm,10 um); mobile phase: [0.10% oNH₃H₂O/EtOH]; B %: 20%-20%). The desiredfraction was concentrated under reduced pressure to yield a residuewhich was dissolved in MeCN (20 mL) and water (20 mL) and lyophilized toyieldN-[1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]prop-2-enamide(44.08 mg, 132.61 μmol, 12.7% yield, 98.2% purity, SFC: R_(t)=2.050,ee=99.88%, [α]^(26.5) _(D)=−32.73 (CHCl₃, c=0.055 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl3) δ ppm 7.57 (d, J=8.2 Hz, 2H), 7.44 (d,J=8.2 Hz, 2H), 6.27 (dd, J=1.4, 17.0 Hz, 1H), 6.13-6.01 (m, 1H), 5.64(dd, J=1.4, 10.4 Hz, 1H), 5.42-5.32 (m, 1H), 3.94-3.77 (m, 1H), 3.47 (q,J=6.7 Hz, 1H), 2.97 (d, J=10.6 Hz, 1H), 2.70 (d, J=11.3 Hz, 1H),2.21-2.06 (m, 2H), 2.00 (d, J=12.5 Hz, 1H), 1.94-1.86 (m, 1H), 1.54-1.39(m, 2H), 1.36 (d, J=6.7 Hz, 3H); ES-LCMS m/z 327.2 [M+H]⁺.

I-44

Step 1: 7-Bromoquinolin-5-ol

A solution of 7-bromo-5-methoxy-quinoline (2 g, 8.40 mmol, 1 eq) in HBr(37.25 g, 184.15 mmol, 25 mL, 40% purity, 21.92 eq) was stirred at 120°C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.35) showed starting material wasconsumed and one major new spot was detected. The reaction mixture wasconcentrated, diluted with H₂O (100 mL) and saturated NaOH (30 mL,adjust pH to 13). The mixture was extracted with PE/EtOAc (4:1, 30mL×2). The aqueous phase was neutralized with 2 N HCl (30 mL, adjust pHto 7) and filtered. The filtered cake was concentrated to yield7-bromoquinolin-5-ol (1 g, 4.02 mmol, 47.8% yield, 90.0% purity) as ayellow solid. 1H NMR (500 MHz, DMSO-d₆) δ ppm 11.07 (br s, 1H), 8.87(dd, J=1.8, 4.2 Hz, 1H), 8.47 (dd, J=0.9, 8.4 Hz, 1H), 7.65 (d, J=1.1Hz, 1H), 7.50 (dd, J=4.3, 8.4 Hz, 1H), 7.04 (d, J=1.7 Hz, 1H); ES-LCMSm/z 223.8, 225.8 [M+H]⁺.

Step 2: 7-Bromo-5-[3-(trifluoromethyl)phenoxy]quinoline

To a solution of 7-bromoquinolin-5-ol (400 mg, 1.61 mmol, 1 eq) in DCM(40 mL) was added Cu(OAc)₂ (583.67 mg, 3.21 mmol, 2 eq),[3-(trifluoromethyl)phenyl]boronic acid (915.50 mg, 4.82 mmol, 96.35 μL,3 eq) and DIEA (622.99 mg, 4.82 mmol, 839.60 μL, 3 eq). The mixture wasstirred under O₂ (15 psi) atmosphere at 25° C. for 12 h. The mixture wasfiltered. The filtrate was diluted with H₂O (20 mL) and extracted withDCM (20 mL×3). The combine organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby preparative TLC (PE/EtOAc=4/1, TLC: PE/EtOAc=4/1, R_(f)=0.45) toyield 7-bromo-5-[3-(trifluoromethyl)phenoxy]quinoline (300 mg, 570.42μmol, 35.5% yield, 70.0% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.01 (dd, J=1.7, 4.1 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H),8.09 (d, J=0.9 Hz, 1H), 7.71-7.66 (m, 1H), 7.64 (dd, J=4.3, 8.5 Hz, 1H),7.45 (d, J=9.0 Hz, 1H), 7.20 (d, J=1.7 Hz, 1H), 7.05 (s, 2H); ES-LCMSm/z 367.7, 369.7 [M+H]⁺.

Step 3: tert-ButylN-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]carbamate

To a mixture of 7-bromo-5-[3-(trifluoromethyl)phenoxy]quinoline (270 mg,513.38 μmol, 1 eq) and tert-butyl carbamate (300.70 mg, 2.57 mmol, 5 eq)in 1,4-dioxane (3 mL) was added Pd(OAc)₂ (11.53 mg, 51.34 μmol, 0.1 eq),XPhos (24.47 mg, 51.34 μmol, 0.1 eq) and Cs₂CO₃ (501.81 mg, 1.54 mmol, 3eq) under N₂ atmosphere. The mixture was stirred under N₂ atmosphere at120° C. for 12 h. The mixture was filtered. The filtrate was dilutedwith H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combine organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated toyield a residue which was purified by flash silica gel chromatography(from pure PE to PE/EtOAc=2/3, TLC: PE/EtOAc=1/1, R_(f)=0.30) to yieldtert-butyl N-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]carbamate (200mg, 395.67 μmol, 77.1% yield, 80.0% purity) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.74 (s, 1H), 8.86 (dd, J=1.7, 4.2 Hz, 1H),8.38-8.31 (m, 1H), 8.04 (s, 1H), 7.70-7.63 (m, 1H), 7.61-7.55 (m, 1H),7.52 (s, 1H), 7.39 (td, J=4.1, 8.3 Hz, 2H), 7.23 (d, J=1.7 Hz, 1H), 1.47(s, 9H); ES-LCMS m z 405.1 [M+H]⁺.

Step 4: 5-[3-(Trifluoromethyl)phenoxy]quinolin-7-amine

To a solution of tert-butylN-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]carbamate (200 mg, 395.67μmol, 1 eq) in DCM (5 mL) was added TFA (1.23 g, 10.80 mmol, 799.98 μL,27.31 eq). The mixture was stirred at 25° C. for 12 h. The reactionmixture was concentrated to yield5-[3-(trifluoromethyl)phenoxy]quinolin-7-amine (200 mg, crude, 2 TFA) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.90 (d, J=7.8 Hz, 1H),8.82 (dd, J=1.3, 5.7 Hz, 1H), 7.81-7.74 (m, 1H), 7.72 (d, J=5.6 Hz, 2H),7.60 (d, J=8.3 Hz, 1H), 7.45 (dd, J=5.7, 7.9 Hz, 1H), 6.71 (d, J=0.7 Hz,1H), 6.48 (d, J=1.5 Hz, 1H); ES-LCMS m/z 305.2 [M+H]⁺.

Step 5: N-[5-[3-(Trifluoromethyl)phenoxy]-7-quinolyl]prop-2-enamide

To a solution of 5-[3-(trifluoromethyl)phenoxy]quinolin-7-amine (200 mg,375.72 μmol, 1 eq, 2 TFA) in DCM (2 mL) was added DIEA (242.80 mg, 1.88mmol, 327.22 μL, 5 eq) and prop-2-enoyl chloride (68.01 mg, 751.44 μmol,61.27 μL, 2 eq). The mixture was stirred at 25° C. for 1 h. The mixturewas diluted with H₂O (20 mL) and extracted with DCM (20 mL×3). Thecombine organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by preparative TLC(PE/EtOAc=3/1, TLC: PE/EtOAc=3/1, R_(f)=0.45) to yieldN-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]prop-2-enamide (19.64 mg,54.81 μmol, 14.6% yield, 100.0% purity) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ ppm 10.50 (s, 1H), 8.92 (dd, J=1.5, 4.1 Hz, 1H), 8.44(d, J=8.2 Hz, 1H), 8.35 (s, 1H), 7.73-7.67 (m, 1H), 7.65-7.56 (m, 2H),7.47 (dd, J=4.0, 8.3 Hz, 2H), 7.28 (d, J=1.7 Hz, 1H), 6.48-6.38 (m, 1H),6.34-6.24 (m, 1H), 5.80 (dd, J=1.7, 10.1 Hz, 1H); ES-LCMS m/z 359.1[M+H]⁺.

I-123 & I-124

Step 1: 5-[3-(Trifluoromethyl)phenoxy]-7-vinyl-quinoline

To a mixture of 7-bromo-5-[3-(trifluoromethyl)phenoxy]quinoline (300 mg,570.42 μmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(439.27 mg, 2.85 mmol, 483.77 μL, 5 eq) in 1,4-dioxane (5 mL) was addedPd(dppf)Cl₂ (41.74 mg, 57.04 μmol, 0.1 eq) and Cs₂CO₃ (2 M, 855.64 μL, 3eq) under N₂ atmosphere. The mixture was stirred at 80° C. for 0.5 h inmicrowave (0 bar) under N₂ atmosphere. TLC (PE/EtOAc=3/1, R_(f)=0.45)showed starting material was consumed and one major new spot wasdetected. The mixture was diluted with H₂O (10 mL) and extracted withEtOAc (20 mL×3). The combine organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby preparative TLC (PE/EtOAc=4/1, TLC: PE/EtOAc=4/1, R_(f)=0.45) toyield 5-[3-(trifluoromethyl)phenoxy]-7-vinyl-quinoline (160 mg, 355.23μmol, 62.3% yield, 70.0% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.96 (dd, J=1.7, 4.1 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H),7.93 (s, 1H), 7.66-7.59 (m, 1H), 7.56-7.50 (m, 2H), 7.50-7.44 (m, 2H),7.30 (dd, J=2.1, 8.3 Hz, 1H), 6.96 (dd, J=11.0, 17.5 Hz, 1H), 6.01 (d,J=17.5 Hz, 1H), 5.44 (d, J=11.0 Hz, 1H); ES-LCMS m/z 316.0 [M+H]⁺.

Step 2:(5R)-3-Bromo-5-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]-4,5-dihydroisoxazole

To a solution of 5-[3-(trifluoromethyl)phenoxy]-7-vinyl-quinoline (150mg, 333.03 μmol, 1 eq) in EtOAc (3 mL) was added NaHCO₃ (279.78 mg, 3.33mmol, 10 eq) and dibromomethanone oxime (135.10 mg, 666.06 μmol, 2 eq).The mixture was stirred at 25° C. for 12 h. The mixture was diluted withH₂O (5 mL) and extracted with EtOAc (5 mL×3). The combine organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated to yield aresidue which was purified by preparative TLC (PE/EtOAc=3/1, TLC:PE/EtOAc=3/1, R_(f)=0.40) and then by preparative SFC (column: DAICELCHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃.H₂O MeOH];B %: 25%-25%, min) to yield Peak 1 and Peak 2. Peak 1 was concentratedunder reduced pressure to yield a residue which was dissolved in MeCN(20 mL) and H₂O (40 mL) and lyophilized to yield(5R)-3-bromo-5-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]-4,5-dihydroisoxazole(17.01 mg, 38.91 μmol, 11.7% yield, 100.0% purity, SFC: R_(t)=2.421,ee=100%, [α]^(26.9) _(D)=+138.898 (MeOH, c=0.071 g/100 mL)) as colorlessoil. ¹H NMR (500 MHz, CD₃OD) δ ppm 8.95 (dd, J=1.6, 4.3 Hz, 1H), 8.64(d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.65-7.59 (m, 2H), 7.52 (d, J=7.8 Hz,1H), 7.44 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 5.89(dd, J=8.3, 11.1 Hz, 1H), 3.82 (dd, J=11.1, 17.5 Hz, 1H), 3.29-3.24 (m,1H); ES-LCMS m/z 436.9, 438.9 [M+H]⁺. Peak 2 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (20 mL)and H₂O (40 mL) and lyophilized to yield(5S)-3-bromo-5-[5-[3-(trifluoromethyl)phenoxy]-7-quinolyl]-4,5-dihydroisoxazole(18.83 mg, 42.31 μmol, 12.7% yield, 98.2% purity, SFC: R_(t)=2.911,ee=99.72%, [α]^(26.8) _(D)=−143.003 (MeOH, c=0.055 g/100 mL)) ascolorless oil. ¹H NMR (500 MHz, CD₃OD) δ ppm 8.95 (dd, J=1.5, 4.3 Hz,1H), 8.63 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.65-7.59 (m, 2H), 7.52 (d,J=7.9 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.05 (d, J=1.1 Hz,1H), 5.88 (dd, J=8.4, 11.0 Hz, 1H), 3.82 (dd, J=11.0, 17.5 Hz, 1H),3.29-3.25 (m, 1H); ES-LCMS m/z 436.8, 438.8 [M+H]⁺.

I-64

Step1:1-[(3S)-3-[[4-(Trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one

To a solution of 1-[(3S)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (100 mg,642.02 μmol, 1 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (170mg, 711.20 μmol, 109.68 μL, 1.11 eq) in DCM (6 mL) as added DIEA (1.48g, 11.48 mmol, 2 mL, 17.88 eq). The mixture was stirred at 25° C. for 2h. TLC (PE/EtOAc=1/1, R_(f)=0.40) showed one main spot formed. Themixture was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3).The combined organic layer was dried over Na₂SO₄, filtrated andconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 26%-56%, 10 min) andthen lyophilized to yield1-[(3S)-3-[[4-(trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one(15.55 mg, 51.01 μmol, 7.9% yield, 97.9% purity) as a white oil. ¹H NMR(500 MHz, CD₃OD) δ ppm 7.67-7.61 (m, 2H), 7.59-7.53 (m, 2H), 6.64-6.51(m, 1H), 6.25 (ddd, J=1.8, 5.0, 16.8 Hz, 1H), 5.73 (ddd, J=1.8, 6.5,10.5 Hz, 1H), 3.92-3.84 (m, 2H), 3.83-3.75 (m, 1H), 3.72-3.64 (m, 1H),3.64-3.45 (m, 1H), 3.45-3.32 (m, 2H), 2.23-2.07 (m, 1H), 1.97-1.78 (m,1H); ES-LCMS m/z 299.0 [M+H]⁺.

I-65

Step 1: tert-Butyl N-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate

To a solution of tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (500 mg,2.68 mmol, 1 eq) in DCM (20 mL) was added DIEA (2.23 g, 17.22 mmol, 3mL, 6.42 eq) and then prop-2-enoyl chloride (270 mg, 2.98 mmol, 243.24μL, 1.11 eq) was added dropwise at 0° C. under N₂ atmosphere. Themixture was stirred at 0° C. for 1 h. TLC (PE/EtOAc=1/1, R_(f)=0.30)showed one main spot formed. The mixture was diluted with H₂O (20 mL)and extracted with EtOAc (20 mL×3). The combined organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1, R_(f)=0.30) to yieldtert-butyl N-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate (260 mg, 1.08mmol, 40.3% yield, 100.0% purity) as yellow oil. ¹H NMR (500 MHz, CDCl₃)δ ppm 6.49-6.33 (m, 2H), 5.73-5.66 (m, 1H), 3.86-3.71 (m, 1H), 3.70-3.57(m, 2H), 3.48-3.38 (m, 1H), 2.28-2.11 (m, 1H), 2.03-1.75 (m, 1H), 1.46(s, 9H); ES-LCMS m/z 241.2 [M+H]⁺.

Step 2: 1-[(3R)-3-Aminopyrrolidin-1-yl]prop-2-en-1-one

To a solution of tert-butylN-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate (254.80 mg, 1.06 mmol, 1eq) in DCM (6 mL) was added TFA (3.02 g, 26.46 mmol, 1.96 mL, 24.96 eq).The mixture was stirred at 25° C. for 1 h. TLC (PE/EtOAc=1/1,R_(f)=0.20) showed the starting material was consumed completely. Thereaction mixture was concentrated under reduced pressure to yield1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (150 mg, 531.07 μmol,50.1% yield, 90.0% purity, TFA) as yellow oil, which was used in thenext step without further purification. 1H NMR (400 MHz, CDCl₃) δ ppm6.43 (br s, 2H), 6.04-5.89 (m, 1H), 4.37-4.06 (m, 2H), 3.99-3.76 (m,3H), 2.62-2.32 (m, 2H); ES-LCMS m z no desired MS found.

Step 3:1-[(3S)-3-[[3-(trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one

To a solution of 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (150 mg,1.05 mmol, 1 eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (260 mg,1.09 mmol, 165.61 μL, 1.04 eq) in DCM (3 mL) was added DIEA (727 mg,5.63 mmol, 979.78 μL, 5.36 eq). The mixture was stirred at 25° C. for 12h. TLC (PE/EtOAc=1/1, R_(f)=0.30) showed one main spot formed. Thereaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(20 mL×3). The combined organic layers dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um;mobile phase: [water (10 mm NH₄HCO₃)-ACN]; B %: 27%-57%, 10 min); B %:35%-65%, 10 min) and then lyophilized to yield1-[(3S)-3-[[3-(trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one(17.66 mg, 59.20 μmol, 5.6% yield, 100.0% purity) as white oil. ¹H NMR(500 MHz, CD₃OD) δ ppm 7.72 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.59-7.50(m, 2H), 6.58 (dt, J=10.5, 17.4 Hz, 1H), 6.29-6.23 (m, 1H), 5.73 (ddd,J=1.8, 4.4, 10.5 Hz, 1H), 3.93-3.86 (m, 2H), 3.86-3.76 (m, 1H),3.73-3.37 (m, 4H), 2.23-2.10 (m, 1H), 1.99-1.79 (m, 1H); ES-LCMS m/z299.1 [M+H]⁺.

I-125, I-126, I-127, & I-148

Step 1:3-Chloro-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole

To a solution of3-bromo-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(1 g, 2.25 mmol, 1 eq) in 1,4-dioxane (20 ml) was added HCl (229.50 g,251.78 mmol, 225.00 ml, 4 N, 111.95 eq). The mixture was stirred at 40°C. for 12 h. The reaction mixture was quenched by addition of water (50mL), extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.55) to yield3-chloro-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(640 mg, 1.46 mmol, 64.8% yield, 81% purity) as white oil. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.63-7.55 (m, 1H), 7.48-7.39 (m, 2H), 7.24-7.19 (m,2H), 7.15 (d, J=8.3 Hz, 1H), 7.07 (d, J=1.2 Hz, 1H), 5.76 (t, J=10.1 Hz,1H), 4.02 (q, J=7.1 Hz, 1H), 3.70 (dd, J=10.8, 17.4 Hz, 1H), 2.16 (s,3H); ES-LCMS m/z 356.1, 358.1 [M+H]⁺.

Step 2:(5S)-5-[4-Methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-2-yl)-4,5-dihydroisoxazole&(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-1-yl)-4,5-dihydroisoxazole&(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-2-yl)-4,5-dihydroisoxazole&(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-1-yl)-4,5-dihydroisoxazole

To a solution of3-chloro-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-4,5-dihydroisoxazole(300 mg, 683.09 μmol, 1 eq) in DMF (7 mL) was added Cs₂CO₃ (667.69 mg,2.05 mmol, 3 eq) and 1H-triazole (235.89 mg, 3.42 mmol, 198.22 μL, 5eq). The mixture was stirred at 110° C. for 12 h. The reaction mixturewas quenched by addition of water (50 mL), extracted with EtOAc (30mL×3). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.45) to yield thecompound which was separated by SFC (column: DAICEL CHIRALCEL OJ-H (250mm*30 mm, 5 μm); mobile phase: [Neu-EtOH]; B %: 20%-20%, min) to yield(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-2-yl)-4,5-dihydroisoxazole(57.56 mg, 148.22 μmol, 21.7% yield, 100% purity, SFC: R_(t)=2.812 min,ee=100%, [α]^(26.1) _(D)=−185.71, MeOH, c=0.042 g/100 mL)) as white oil.¹H NMR (500 MHz, CDCl₃) δ ppm 7.87 (s, 2H), 7.43-7.39 (m, 1H), 7.34-7.30(m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.16 (s, 1H), 7.03 (s, 2H), 5.86 (t,J=9.9 Hz, 1H), 4.07 (dd, J=10.9, 17.3 Hz, 1H), 3.65 (dd, J=9.0, 17.4 Hz,1H), 2.23 (s, 3H); ES-LCMS m/z 389.2 [M+H]⁺ and(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-1-yl)-4,5-dihydroisoxazole(25.55 mg, 65.79 μmol, 9.6% yield, 100% purity, SFC: R_(t)=3.103 min,ee=100%, [α]^(26.1) _(D)=+139.13, MeOH, c=0.023 g/100 ml) as white oil.¹H NMR (500 MHz, CDCl₃) δ ppm 8.29 (s, 1H), 7.83 (s, 1H), 7.45-7.40 (m,1H), 7.37-7.31 (m, 2H), 7.21-7.16 (m, 2H), 7.05-7.00 (m, 2H), 5.90-5.84(m, 1H), 4.15 (dd, J=10.9, 17.6 Hz, 1H), 3.74 (dd, J=9.0, 17.5 Hz, 1H),2.24 (s, 3H); ES-LCMS m/z 389.2 [M+H]⁺ and(5R)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-2-yl)-4,5-dihydroisoxazole(53.29 mg, 131.87 μmol, 19.3% yield, 96.1% purity, SFC: R_(t)=3.348 min,ee=99.84%, [α]^(26.1) _(D)=+158.14, MeOH, c=0.042 g/100 mL)) as whiteoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (s, 2H), 7.44-7.38 (m, 1H),7.35-7.30 (m, 2H), 7.22 (dd, J=1.5, 7.8 Hz, 1H), 7.16 (s, 1H), 7.03 (d,J=1.5 Hz, 2H), 5.85 (dd, J=9.3, 10.8 Hz, 1H), 4.07 (dd, J=10.9, 17.2 Hz,1H), 3.65 (dd, J=9.0, 17.4 Hz, 1H), 2.23 (s, 3H); ES-LCMS m/z 389.2[M+H]⁺ and(5S)-5-[4-methyl-3-[3-(trifluoromethyl)phenoxy]phenyl]-3-(triazol-1-yl)-4,5-dihydroisoxazole(20.17 mg, 51.58 μmol, 7.5% yield, 99.3% purity, SFC: R_(t)=3.489 min,ee=99.66%, [α]^(26.1) _(D)=−139.13, MeOH, c=0.023 g/100 mL)) as whiteoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.29 (d, J=1.2 Hz, 1H), 7.82 (d,J=1.2 Hz, 1H), 7.45-7.39 (m, 1H), 7.36-7.30 (m, 2H), 7.21-7.16 (m, 2H),7.05-7.00 (m, 2H), 5.87 (dd, J=9.2, 10.6 Hz, 1H), 4.15 (dd, J=10.9, 17.5Hz, 1H), 3.74 (dd, J=9.0, 17.6 Hz, 1H), 2.24 (s, 3H); ES-LCMS m/z 389.2[M+H]⁺.

I-66

Step 1: N-[1-(1-Naphthyl)-4-piperidyl]prop-2-enamide

A mixture of N-(4-piperidyl)prop-2-enamide (500 mg, 1.84 mmol, 1 eq,HCl), 1-naphthylboronic acid (378.85 mg, 2.20 mmol, 1.2 eq), Cu(OAc)₂(666.83 mg, 3.67 mmol, 2 eq) and DIEA (1.19 g, 9.18 mmol, 1.60 mL, 5 eq)in DCM (10 mL) was degassed and purged with N₂ for 3 times and then themixture was stirred under N₂ atmosphere at 25° C. for 12 h. TLC(PE/EtOAc=1/1, R_(f)=0.42) showed one new spot was formed. The mixturewas filtered and the filtrate was concentrated to give the residue whichwas purified by flash silica gel chromatography (from PE/EtOAc=100/1 to1/1) to give crude product which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water (0.05%NH₃.H₂O+10 mM NH₄HCO₃)-ACN]; B %: 37%-67%, 10 min) to yieldN-[1-(1-naphthyl)-4-piperidyl]prop-2-enamide (11.50 mg, 41.02 μmol, 2.2%yield, 100.0% purity) as a red solid. ¹H NMR (400 MHz, CDCl₃) δ ppm8.17-8.14 (m, 1H), 7.85-7.82 (m, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.50-7.44(m, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.10 (d, J=6.7 Hz, 1H), 6.35 (dd,J=1.4, 17.0 Hz, 1H), 6.32-6.10 (m, 1H), 5.68 (dd, J=1.2, 10.2 Hz, 1H),5.54 (s, 1H), 4.20-4.10 (m, 1H), 3.41-3.38 (m, 2H), 2.97-2.91 (m, 2H),2.21-2.18 (m, 2H), 1.88-1.79 (m, 2H); ES-LCMS m/z 281.1 [M+H]⁺.

I-150 & I-151

Step 1: tert-Butyl 4-isopropenylpiperidine-1-carboxylate

To a solution of methyl(triphenyl)phosphonium; bromide (1.12 g, 3.15mmol, 1.3 eq) in THE (10 mL) was cooled to −78° C. then added n-BuLi(2.5 M, 1.45 mL, 1.5 eq) dropwise under N₂ atmosphere. The mixture wasstirred at 0° C. for 0.5 h under N₂ atmosphere. The mixture was cooledto −78° C. and a solution of tert-butyl 4-acetylpiperidine-1-carboxylate(550 mg, 2.42 mmol, 1 eq) in THE (5 mL) was added slowly. The mixturewas stirred at 28° C. for 4 h under N₂ atmosphere. The reaction mixturewas diluted with water (50 mL) then extracted with EtOAc (30 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=5/1, R_(f)=0.65) to yield tert-butyl4-isopropenylpiperidine-1-carboxylate (350 mg, 1.55 mmol, 64.2% yield,100.0% purity) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm4.72-4.65 (m, 2H), 4.07-3.90 (m, 2H), 2.67-2.50 (m, 2H), 2.0-1.95 (m,1H), 1.68 (s, 3H), 1.67-1.63 (m, 2H), 1.38 (s, 9H), 1.23-1.13 (m, 2H)

Step 2: tert-Butyl4-(3-bromo-5-methyl-4H-isoxazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-isopropenylpiperidine-1-carboxylate (300mg, 1.33 mmol, 1 eq) and dibromomethanone oxime (270.05 mg, 1.33 mmol, 1eq) in EtOAc (10 mL) was added NaHCO₃ (1.12 g, 13.31 mmol, 10 eq). Themixture was stirred at 25° C. for 12 h under N₂ atmosphere. The reactionmixture was diluted with water (50 mL) then extracted with EtOAc (30mL×3). The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated to yield a residue which was purified byflash silica gel chromatography (from PE/EtOAc=100/1 to 2/1, TLC:PE/EtOAc=1/1, R_(f)=0.45) to yield tert-butyl4-(3-bromo-5-methyl-4H-isoxazol-5-yl)piperidine-1-carboxylate (370 mg,948.3 μmol, 71.2% yield, 89.0% purity) as light yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 4.31-4.14 (m, 2H), 3.08-3.06 (m, 1H), 2.83-2.78 (m,1H), 2.66-2.63 (m, 2H), 1.74-1.62 (m, 3H), 1.47 (s, 9H), 1.39 (s, 3H),1.27 (t, J=7.1 Hz, 1H), 1.23-1.19 (m, 1H); ES-LCMS m/z 347.1, 348.1[M+H]⁺.

Step 3: 3-Bromo-5-methyl-5-(4-piperidyl)-4H-isoxazole

To a solution of tert-butyl4-(3-bromo-5-methyl-4H-isoxazol-5-yl)piperidine-1-carboxylate (370 mg,948.32 μmol, 1 eq) in DCM (6 mL) was added TFA (108.13 mg, 948.32 μmol,70.21 μL, 1 eq). The mixture was stirred at 25° C. for 1 h under N₂atmosphere. The reaction mixture was diluted with water (50 mL) thenextracted with EtOAc (30 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated to yield aresidue which was 3-bromo-5-methyl-5-(4-piperidyl)-4H-isoxazole (300 mg,805.75 μmol, 85.0% yield, 97.0% purity, TFA) as yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.56 (s, 1H), 3.32 (d, J=12.2 Hz, 2H), 2.84 (t,J=10.5 Hz, 2H), 2.75-2.60 (m, 1H), 2.48-2.37 (m, 1H), 1.94-1.83 (m, 1H),1.77 (t, J=13.3 Hz, 2H), 1.51-1.35 (m, 2H), 1.34-1.29 (m, 3H); ES-LCMSm/z 247.1 [M+H]⁺.

Step 4:(5R)-3-Bromo-5-methyl-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4H-isoxazole&(5S)-3-Bromo-5-methyl-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4H-isoxazole

To a solution of 3-bromo-5-methyl-5-(4-piperidyl)-4H-isoxazole (300 mg,830.67 μmol, 1 eq, TFA) in DCM (15 mL) was added DIEA (536.79 mg, 4.15mmol, 723.44 μL, 5 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene(218.41 mg, 913.74 μmol, 140.91 μL, 1.1 eq) The mixture was stirred at25° C. for 12 h under N₂ atmosphere. The reaction mixture was dilutedwith water (50 mL) then extracted with EtOAc (30 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=1/1,R_(f)=0.45) to yield which was separated by SFC (column: DAICELCHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O MeOH]; B%: 15%-15%, min) to yield Peak 1 and Peak 2. Peak 1 was concentratedunder reduced pressure to yield a residue which was lyophilized to yield(5R)-3-bromo-5-methyl-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4H-isoxazole(40 mg, 98.70 μmol, 11.9% yield, 100.0% purity, SFC: R_(t)=2.693 min,ee=99.4%, [α]^(25.9) _(D)=+40.0, MeOH, c=0.025 g/100 mL) as colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.65-7.60 (m, 2H), 7.53 (d, J=7.8 Hz,2H), 3.59 (s, 2H), 3.20 (d, J=17.6 Hz, 1H), 2.97 (d, J=11.0 Hz, 2H),2.91 (d, J=17.6 Hz, 1H), 2.03 (t, J=11.7 Hz, 2H), 1.75-1.57 (m, 3H),1.44-1.36 (m, 2H), 1.35 (s, 3H); ES-LCMS m/z 405.1, 406.1 [M+H]⁺. Peak 1was concentrated under reduced pressure to yield a residue which waslyophilized to yield(5S)-3-bromo-5-methyl-5-[1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4H-isoxazole(42 mg, 103.64 μmol, 12.5% yield, 100.0% purity, SFC: R_(t)=2.903 min,ee=93.7%, [α]^(25.9) _(D)=−51.6, MeOH, c=0.031 g/100 mL) as colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.65-7.61 (m, 2H), 7.55-7.51 (m, 2H),3.59 (s, 2H), 3.20 (d, J=17.6 Hz, 1H), 2.97 (d, J=12.0 Hz, 2H), 2.91 (d,J=17.6 Hz, 1H), 2.03 (t, J=11.9 Hz, 2H), 1.74-1.57 (m, 3H), 1.45-1.36(m, 2H), 1.35 (s, 3H); ES-LCMS m/z 405.1, 406.1 [M+H]⁺.

I-67

Step 1: Tert-butyl N-(4-hydroxycyclohexyl)carbamate

To a solution of 4-aminocyclohexanol (200 mg, 1.74 mmol, 1 eq) in EtOH(5 mL) was added tert-butoxycarbonyl tert-butyl carbonate (1.14 g, 5.21mmol, 1.20 mL, 3 eq). The mixture was stirred at 29° C. for 12 h. TLC(PE/EtOAc=1/0, R_(f)=0.70) showed starting material was remained and onenew spot was detected. The mixture was evaporated to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1, R_(f)=0.40) to yieldtert-butyl N-(4-hydroxycyclohexyl)carbamate (240 mg, 1.11 mmol, 64.2%yield, 100% purity) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm6.66 (d, J=7.9 Hz, 1H), 4.49 (d, J=4.4 Hz, 1H), 3.13 (s, 1H), 1.79-1.68(m, 4H), 1.37 (s, 9H), 1.14 (t, J=9.5 Hz, 4H); ES-LCMS no desired m zwas detected.

Step 2: 4-[4-(Trifluoromethyl)phenoxy]cyclohexanamine

To a stirred solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate(200 mg, 836.09 μmol, 1 eq) in DMF (6 mL) was added NaH (83.60 mg, 2.09mmol, 60%, 2.5 eq) at 0° C. for 0.5 h. Then1-fluoro-4-(trifluoromethyl)benzene (205.80 mg, 1.25 mmol, 159.54 μL,1.5 eq) was added to the reaction mixture and stirred at 80° C. for 12 hunder N₂ atmosphere. The reaction mixture was diluted with H₂O (10 mL)and extracted with DCM and isopropanol (V_((DCM)):V_((isopropanol))=3:1; 20 mL×3). The combined organic layers were washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from DCM/MeOH=100/1 to 10/1, DCM/MeOH=100/1 to 10/1,R_(f)=0.38) to yield 4-[4-(trifluoromethyl)phenoxy]cyclohexanamine (60mg, 196.71 μmol, 23.5% yield, 85.0% purity) as brown oil. ¹H NMR (400MHz, CDCl₃) δ ppm 7.52 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H),4.33-4.23 (m, 1H), 2.94 (d, J=9.3 Hz, 1H), 2.17 (d, J=10.8 Hz, 2H), 2.05(d, J=11.5 Hz, 2H), 1.60-1.49 (m, 2H), 1.47-1.36 (m, 2H); ES-LCMS m/z260.2 [M+H]⁺.

Step 3: N-[4-[4-(Trifluoromethyl)phenoxy]cyclohexyl]prop-2-enamide

To a stirred solution of 4-[4-(trifluoromethyl)phenoxy]cyclohexanamine(60 mg, 196.71 μmol, 1 eq) and prop-2-enoyl chloride (23.14 mg, 255.72μmol, 20.85 μL, 1.3 eq) in THF (4 mL) was added Et₃N (59.71 mg, 590.13μmol, 82.14 μL, 3 eq). The reaction mixture was stirred at 25° C. for 12h under N₂ atmosphere. The reaction mixture was diluted with H₂O (10 mL)and extracted with EtOAc (20 mL×3). The combined organic layers werewashed with brine (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified bypreparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 36%-56%, 10 min) to yieldN-[4-[4-(trifluoromethyl)phenoxy]cyclohexyl]prop-2-enamide (16.61 mg,51.75 μmol, 26.3% yield, 97.6% purity) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.04 (d, J=6.9 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.14(d, J=8.5 Hz, 2H), 6.27-6.18 (m, 1H), 6.11-6.04 (m, 1H), 5.56 (dd,J=2.2, 10.1 Hz, 1H), 4.49-4.40 (m, 1H), 3.72-3.62 (m, 1H), 2.12-2.03 (m,2H), 1.88 (d, J=9.8 Hz, 2H), 1.52-1.43 (m, 2H), 1.43-1.33 (m, 2H);ES-LCMS m/z 314.3 [M+H]⁺.

I-68 & I-203

Step 1: 1-[[4-(Trifluoromethyl)phenyl]methyl]-2,3-dihydroquinolin-4-one

To a solution of 2,3-dihydro-1H-quinolin-4-one (200 mg, 1.36 mmol, 1 eq)in MeCN (5 mL) was added 1-(bromomethyl)-4-(trifluoromethyl)benzene(389.80 mg, 1.63 mmol, 251.48 μL, 1.2 eq) and DIEA (175.63 mg, 1.36mmol, 236.70 μL, 1 eq). The mixture was stirred at 120° C. for 1.5 hunder microwave. The reaction mixture was concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.42) to yield1-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydroquinolin-4-one (370 mg,1.19 mmol, 87.4% yield, 98.0% purity) as a yellow solid. 1H NMR (500MHz, CDCl₃) δ ppm 7.95 (dd, J=1.7, 7.9 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H),7.43 (d, J=7.9 Hz, 2H), 7.32 (ddd, J=1.7, 7.1, 8.6 Hz, 1H), 6.77 (t,J=7.4 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.62 (s, 2H), 3.67-3.58 (m, 2H),2.84-2.74 (m, 2H); ES-LCMS m/z 306.1 [M+H]⁺.

Step 2:1-[[4-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-amine

To a stirred solution of1-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydroquinolin-4-one (300 mg,963.01 μmol, 1 eq) and ammonia; formic acid (850.12 mg, 13.48 mmol, 14eq) in MeOH (6 mL) was stirred at 60° C. for 1 h. Then NaBH₃CN (302.58mg, 4.82 mmol, 5 eq) was added to the reaction mixture and stirred at60° C. for 12 h. The reaction mixture was concentrated under reducedpressure to remove MeOH. The residue was diluted with EtOAc (25 mL),then adjust pH to 2 with 6 N HCl and stirred at 25° C. for 1 h andextracted with H₂O (15 mL×1). The combined water layers were washed withsat. aq. NaOH to adjust pH to 9, then extracted with EtOAc (20 mL×2).The combined organic layers were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was used in the next step without further purification toyield1-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-amine(160 mg, 417.86 μmol, 43.4% yield, 80.0% purity) as red oil. ¹H NMR (400MHz, CDCl₃) δ ppm 7.57 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.24(dd, J=1.2, 7.6 Hz, 1H), 7.07-7.01 (m, 1H), 6.67 (dt, J=1.0, 7.3 Hz,1H), 6.44 (d, J=8.3 Hz, 1H), 4.55 (s, 2H), 4.08 (t, J=4.6 Hz, 1H),3.60-3.51 (m, 1H), 3.37-3.29 (m, 1H), 2.19-2.06 (m, 1H), 1.95-1.85 (m,1H); ES-LCMS no desired m z was detected.

Step 3:N-[(4S)-1-[[4-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-yl]prop-2-enamide&N-[(4R)-1-[[4-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-yl]prop-2-enamide

To a stirred solution of1-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-amine(110 mg, 287.28 μmol, 1 eq) and prop-2-enoyl chloride (39.00 mg, 430.92μmol, 35.14 μL, 1.5 eq) in THE (5 mL) was added Et₃N (87.21 mg, 861.83μmol, 119.96 μL, 3 eq). The reaction mixture was stirred at 25° C. for12 h under N₂ atmosphere. The reaction mixture was concentrated underreduced pressure to remove THF. The residue was diluted with dilutedwith H₂O (15 mL) and extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by preparative HPLC (column: Phenomenex Synergi C18150*30 mm*4 μm; mobile phase: [water (0.05% HCl)-ACN]; B %: 56%-76%, 10min) to yield crude product which was separated by chiral SFC (column:DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂OETOH]; B %: 20%-20%, min) to yield Peak 1 and Peak 2. Peak 1 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yieldN-[(4S)-1-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-yl]prop-2-enamide(27.99 mg, 77.00 μmol, 26.8% yield, 99.1% purity, SFC: R_(t)=2.763 min,ee=99.0%, [α]^(27.8) _(D)=+140 (MeOH, c=0.05 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59 (d, J=8.1 Hz, 2H), 7.38 (d,J=8.1 Hz, 2H), 7.19 (d, J=7.6 Hz, 1H), 7.11-7.05 (m, 1H), 6.72-6.64 (m,1H), 6.49 (d, J=8.1 Hz, 1H), 6.34 (dd, J=1.2, 17.1 Hz, 1H), 6.14-6.05(m, 1H), 5.75 (d, J=6.8 Hz, 1H), 5.69 (dd, J=1.2, 10.3 Hz, 1H),5.27-5.19 (m, 1H), 4.60-4.47 (m, 2H), 3.43-3.35 (m, 2H), 2.26-2.15 (m,2H); ES-LCMS m/z 361.2 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(40 mL) and lyophilized to yieldN-[(4R)-1-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-4-yl]prop-2-enamide(26.43 mg, 72.77 μmol, 25.3% yield, 99.2% purity SFC: R_(t)=3.020 min,ee=98.46%, [α]^(27.7) _(D)=−104.348 (MeOH, c=0.046 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59 (d, J=8.1 Hz, 2H), 7.38 (d,J=8.1 Hz, 2H), 7.19 (d, J=7.6 Hz, 1H), 7.12-7.05 (m, 1H), 6.68 (t, J=7.3Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 6.34 (dd, J=1.3, 17.0 Hz, 1H),6.15-6.05 (m, 1H), 5.76 (d, J=6.8 Hz, 1H), 5.69 (dd, J=1.5, 10.3 Hz,1H), 5.28-5.19 (m, 1H), 4.61-4.47 (m, 2H), 3.43-3.34 (m, 2H), 2.26-2.15(m, 2H); ES-LCMS m/z 361.2 [M+H]⁺.

I-129 & I-130

Step 1: 5-Bromo-2-methyl-3-[3-(trifluoromethyl)phenoxy]pyridine

To a stirred solution of 5-bromo-2-methyl-pyridin-3-ol (500 mg, 2.66mmol, 1 eq) in DMSO (30 mL) was added K₃PO₄ (1.13 g, 5.32 mmol, 2 eq),CuI (50.65 mg, 265.93 μmol, 0.1 eq), pyridine-2-carboxylic acid (32.74mg, 265.93 μmol, 0.1 eq) and 1-iodo-3-(trifluoromethyl)benzene (868.00mg, 3.19 mmol, 459.26 μL, 1.2 eq). The reaction mixture was at 120° C.for 12 h under N₂ atmosphere. The reaction mixture was diluted withEtOAc (50 mL) then washed with saturated NaCl solution (30 mL×2). Theaqueous phase was extracted with EtOAc (50 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.35) to yield5-bromo-2-methyl-3-[3-(trifluoromethyl)phenoxy]pyridine (220 mg, 638.57μmol, 24.0% yield, 96.4% purity) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.61-8.43 (m, 1H), 7.80-7.69 (m, 1H), 7.67-7.60 (m, 1H),7.58-7.51 (m, 1H), 7.41 (d, J=10.8 Hz, 1H), 7.33-7.22 (m, 1H), 2.39-2.31(m, 3H); ES-LCMS m/z 332.0, 334.0 [M+H]⁺.

Step 2: 2-Methyl-3-[3-(trifluoromethyl)phenoxy]-5-vinyl-pyridine

To a solution of 5-bromo-2-methyl-3-[3-(trifluoromethyl)phenoxy]pyridine(220 mg, 638.57 μmol, 1 eq) in 1,4-dioxane (3 mL) and water (1 mL) wasadded Pd(dppf)Cl₂ (46.72 mg, 63.86 μmol, 0.1 eq), Cs₂CO₃ (624.18 mg,1.92 mmol, 3 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(118.02 mg, 766.29 μmol, 129.98 μL, 1.2 eq). The mixture was bubbledwith N₂ for 3 min and stirred at 100° C. for 30 min under microwave. Thereaction mixture was diluted with EtOAc (15 mL) and filtered through apad of celite. The filtrate was concentrated under reduced pressure togive a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.25) to yield2-methyl-3-[3-(trifluoromethyl)phenoxy]-5-vinyl-pyridine (150 mg, 510.28μmol, 79.9% yield, 95.0% purity) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.45 (d, J=1.4 Hz, 1H), 7.66-7.59 (m, 2H), 7.49 (d, J=7.8Hz, 1H), 7.32 (s, 1H), 7.20 (dd, J=1.8, 8.2 Hz, 1H), 6.74 (dd, J=11.1,17.7 Hz, 1H), 5.94 (d, J=17.7 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 2.36 (s,3H); ES-LCMS m/z 280.2 [M+H]⁺.

Step 3:(5R)-3-Bromo-5-[6-methyl-5-[3-(trifluoromethyl)phenoxy]-3-pyridyl]-4,5-dihydroisoxazole&(5S)-3-bromo-5-[6-methyl-5-[3-(trifluoromethyl)phenoxy]-3-pyridyl]-4,5-dihydroisoxazole

To a stirred solution of2-methyl-3-[3-(trifluoromethyl)phenoxy]-5-vinyl-pyridine (150 mg, 483.43μmol, 1 eq) in EtOAc (5 mL) was added NaHCO₃ (406.13 mg, 4.83 mmol,188.02 μL, 10 eq) and dibromomethanone oxime (147.08 mg, 725.14 μmol,1.5 eq). The reaction mixture was at 25° C. for 12 h under N₂atmosphere. The reaction mixture was diluted with EtOAc (50 mL) thenwashed with saturated NaCl solution (30 mL×2). The aqueous phase wasextracted with EtOAc (50 mL×2). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=2/1, R_(f)=0.30) then separated bySFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um); mobile phase:[0.1% NH₃H₂O EtOH]; B %: 35%-35%, min) to yield peak 1 and peak 2. Peak1 was concentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (10 mL) and lyophilized to yield(5R)-3-bromo-5-[6-methyl-5-[3-(trifluoromethyl)phenoxy]-3-pyridyl]-4,5-dihydroisoxazole(25 mg, 62.32 μmol, 12.9% yield, 100.0% purity, SFC: R_(t)=2.698,ee=99.4%, [α]^(26.1) _(D)=+109.6 (MeOH, c=0.052 g/100 mL)) as yellowoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.33 (d, J=1.7 Hz, 1H), 7.51-7.45 (m,1H), 7.43-7.38 (m, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.20 (s, 1H), 7.07 (d,J=8.3 Hz, 1H), 5.69 (dd, J=9.0, 10.5 Hz, 1H), 3.66 (dd, J=10.9, 17.2 Hz,1H), 3.18 (dd, J=8.8, 17.1 Hz, 1H), 2.52 (s, 3H), 2.54-2.50 (m, 1H);ES-LCMS m/z 401.1, 403.1 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(10 mL) and lyophilized to yield(5S)-3-bromo-5-[6-methyl-5-[3-(trifluoromethyl)phenoxy]-3-pyridyl]-4,5-dihydroisoxazole(25 mg, 62.32 μmol, 12.9% yield, 100.0% purity, SFC: R_(t)=4.388,ee=99.8%, [α]^(26.1) _(D)=−118.5 (MeOH, c=0.054 g/100 mL)) as yellowoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.33 (d, J=1.7 Hz, 1H), 7.52-7.45 (m,1H), 7.43-7.38 (m, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.20 (s, 1H), 7.07 (d,J=8.3 Hz, 1H), 5.69 (dd, J=8.9, 10.6 Hz, 1H), 3.66 (dd, J=10.9, 17.2 Hz,1H), 3.18 (dd, J=8.8, 17.4 Hz, 1H), 2.52 (s, 3H); ES-LCMS m/z 401.1,403.1 [M+H]⁺.

I-69

Step 1: tert-ButylN-[(1R,5S)-3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate

To a solution of tert-butylN-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (40 mg, 201.75 μmol,1 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (48.23 mg, 201.75μmol, 31.11 μL, 1 eq) in DCM (5 mL) was added DIEA (52.15 mg, 403.51μmol, 70.28 μL, 2 eq). The mixture was stirred at 25° C. for 16 h. Thesolvent was removed to give a residue which was purified by preparativeTLC (PE/EtOAc=3/1, R_(f)=0.45) to yield tert-butylN-[(1R,5S)-3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate(66 mg, 181.49 μmol, 89.9% yield, 98.0% purity) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.53 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H),4.59 (br s, 1H), 3.60 (s, 2H), 3.06 (d, J=8.9 Hz, 2H), 2.90 (br s, 1H),2.40-2.38 (m, 2H), 1.53-1.50 (m, 2H), 1.44 (s, 9H); ES-LCMS m/z 357.2[M+H]⁺.

Step 2:(1R,5S)-3-[[4-(Trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-amine

A mixture of tert-butylN-[(1R,5S)-3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate(66 mg, 181.49 μmol, 1 eq) in HCl/MeOH (5 mL, 4 M) was stirred at 25° C.for 1 h. The reaction mixture was concentrated to yield(1R,5S)-3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-amine(58 mg, 178.32 μmol, 98.3% yield, 90.0% purity, HCl) as a white solid.¹H NMR (500 MHz, CD₃OD) δ ppm 7.85-7.79 (m, 4H), 4.51 (br s, 2H),3.74-3.65 (m, 4H), 3.25-3.23 (m, 1H), 2.34-2.31 (m, 2H); ES-LCMS m/z257.2 [M+H]⁺.

Step 3:N-[(1R,5S)-3-[[4-(Trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of(1R,5S)-3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-amine(58 mg, 203.69 μmol, 1 eq) and DIEA (78.98 mg, 611.08 μmol, 106.44 μL, 3eq) in DCM (5 mL) was added prop-2-enoyl chloride (18.44 mg, 203.69μmol, 16.61 μL, 1 eq) at 0° C. The mixture was stirred at 0° C. for 30min. The mixture was concentrated under reduced pressure to give aresidue which was purified by preparative HPLC (column: Agela DuraShellC18 150*25 mm*5 um; mobile phase: [water (0.05% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 36%-66%, 10 min), followed by lyophilization toyieldN-[(1R,5S)-3-[[4-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(28.3 mg, 91.20 μmol, 44.8% yield, 100% purity, SFC: R_(t)=3.013,ee=100%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.54 (d, J=7.9Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 6.27 (dd, J=1.1, 16.9 Hz, 1H), 6.01(dd, J=10.4, 16.9 Hz, 1H), 5.62 (d, J=10.4 Hz, 1H), 5.52 (br s, 1H),3.62 (s, 2H), 3.17-3.08 (m, 3H), 2.42 (d, J=8.4 Hz, 2H), 1.57-1.55 (m,2H); ES-LCMS m/z 311.2 [M+H]⁺.

I-131 & I-132

Step 1: 4-Amino-N-methyl-3-vinylbenzenesulfonamide

To a solution of 4-amino-3-bromo-N-methyl-benzenesulfonamide (1 g, 3.77mmol, 1 eq) in 1,4-dioxane (20 mL) and H₂O (4 mL) was added Pd(dppf)Cl₂(137.99 mg, 188.59 μmol, 0.05 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (668.05 mg, 4.34 mmol,735.73 μL, 1.15 eq) and Cs₂CO₃ (2.46 g, 7.54 mmol, 2.0 eq). The mixturewas stirred under N₂ atmosphere at 100° C. for 16 h. The mixture wasconcentrated, diluted with water (10 mL) and extracted with EtOAc (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 3/1,TLC: PE/EtOAc=3/1, R_(f)=0.6) to yield4-amino-N-methyl-3-vinyl-benzenesulfonamide (700 mg, 2.97 mmol, 78.7%yield, 90.0% purity) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm7.75 (d, J=2.20 Hz, 1H), 7.56 (dd, J=2.20, 8.56 Hz, 1H), 6.74-6.65 (m,2H), 5.72 (dd, J=0.98, 17.36 Hz, 1H), 5.46 (dd, J=0.86, 11.13 Hz, 1H),2.65 (d, J=5.38 Hz, 3H); ES-LCMS m/z 213.1 [M+H]⁺.

Step 2:N-Methyl-4-[4-(trifluoromethyl)anilino]-3-vinyl-benzenesulfonamide

To a solution of 4-amino-N-methyl-3-vinyl-benzenesulfonamide (400 mg,1.70 mmol, 1 eq) in DCM (10 mL) was added Cu(OAc)₂ (462.07 mg, 2.54mmol, 1.5 eq), [4-(trifluoromethyl)phenyl]boronic acid (644.22 mg, 3.39mmol, 2.0 eq) and DIEA (657.58 mg, 5.09 mmol, 886.22 μL, 3.0 eq). Themixture was stirred under O₂ (15 psi) at 30° C. for 48 h. The mixturewas concentrated, diluted with water (10 mL) and extracted with EtOAc(20 mL×3). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated to yield a residue whichwas purified by flash silica gel chromatography (from PE/EtOAc=100/1 to1/1, TLC: PE/EtOAc=1/1, R_(f)=0.3) to yieldN-methyl-4-[4-(trifluoromethyl)anilino]-3-vinyl-benzenesulfonamide (60mg, 151.53 μmol, 8.9% yield, 90.0% purity) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 7.92 (d, J=2.20 Hz, 1H), 7.69 (dd, J=2.20, 8.56 Hz,1H), 7.57 (d, J=8.31 Hz, 2H), 7.39 (d, J=8.56 Hz, 1H), 7.13 (d, J=8.56Hz, 2H), 6.86-6.79 (m, 1H), 6.02 (s, 1H), 5.80 (d, J=0.98 Hz, 1H),5.48-5.56 (m, 1H), 2.71 (d, J=5.38 Hz, 3H); ES-LCMS m/z 357.1 [M+H]⁺.

Step 3:(S)-3-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamideand(R)—3-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide

To a solution of dibromomethanone oxime (36.88 mg, 181.84 μmol, 1.2 eq)in EtOAc (10 mL) was added NaHCO₃ (127.30 mg, 1.52 mmol, 10 eq) andN-methyl-4-[4-(trifluoromethyl)anilino]-3-vinyl-benzenesulfonamide (60mg, 151.53 μmol, 1 eq). The mixture was stirred at 27° C. for 16 h. Themixture was filtered, washed with EtOAc (10 mL×2). The filtrate wasconcentrated to give a residue which was purified by preparative TLC(PE/EtOAc=1/1, R_(f)=0.3) to yield crude product which was separated bychiral SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobilephase: [0.1% NH₃.H₂O EtOH]; B %: 25%-25%) to yield Peak 1 and and Peak2. Peak 1 was concentrated under reduced pressure to yield a residuewhich was dissolved in MeCN (10 mL) and H₂O (10 mL) and lyophilized toyield3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[4-(trifluoromethyl)anilino]benzenesulfonamide(36.25 mg, 73.22 μmol, 48.3% yield, 96.6% purity, SFC: R_(t)=4.484,ee=99.5%, [α]^(26.1) _(D)=−52.0 (CH₃OH, c=0.05 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84-7.74 (m, 2H), 7.59 (d, J=8.61Hz, 2H), 7.51 (d, J=8.61 Hz, 1H), 7.14 (d, J=8.22 Hz, 2H), 6.69 (s, 1H),5.78 (t, J=11.15 Hz, 1H), 4.30 (d, J=5.48 Hz, 1H), 3.52 (d, J=11.35 Hz,2H), 2.70 (d, J=5.48 Hz, 3H); ES-LCMS m/z 478.0, 480.0 [M+H]⁺. Peak 2was concentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and H₂O (10 mL) and lyophilized to yield3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[4-(trifluoromethyl)anilino]benzenesulfonamide(20.6 mg, 40.92 μmol, 27.0% yield, 95.0% purity, SFC: R_(t)=4.281,ee=98.1%, [α]^(26.1) _(D)=+44.0 (CH₃OH, c=0.05 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84-7.74 (m, 2H), 7.59 (d, J=8.61Hz, 2H), 7.51 (d, J=8.61 Hz, 1H), 7.14 (d, J=8.22 Hz, 2H), 6.69 (s, 1H),5.78 (t, J=11.15 Hz, 1H), 4.30 (d, J=5.48 Hz, 1H), 3.52 (d, J=11.35 Hz,2H), 2.70 (d, J=5.48 Hz, 3H); ES-LCMS m/z 478.0, 480.0 [M+H]⁺.

I-152 & I-153

Step 1:3-Bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 3-bromo-5-(4-piperidyl)-4, 5-dihydroisoxazole (520 mg,1.35 mmol, 1.06 eq, TFA) and[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]methanesulfonate (380 mg, 1.27mmol, 1.0 eq) in DMF (3 mL) was added Cs₂CO₃ (1.25 g, 3.82 mmol, 3 eq).The mixture was stirred at 28° C. for 48 h. The reaction mixture wasquenched by addition of H₂O (20 mL) and extracted with EtOAc (20 mL×3).The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue which was purified by preparative HPLC (column: Welch XtimateC18 150*25 mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:50%-80%, 10 min) to yield3-bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(250 mg, 616.90 μmol, 48.4% yield, 100.0% purity) as a white solid.ES-LCMS m/z 407.1 [M+H]⁺.

Step 2:(5S)-3-bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazoleand(5R)-3-bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole

3-bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(250 mg, 616.90 μmol, 1 eq) was separated by SFC (column: DAICELCHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃.H₂O-MeOH]; B%: 20%-20%) to yield peak 1 and peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (15 mL)and water (15 mL) and lyophilized to yield(5S)-3-bromo-5-[1-[(JR)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(30.1 mg, 73.68 μmol, 11.9% yield, 99.2% purity, SFC: R_(t)=2.431,Dr=99.7%, [α]^(26.9) _(D)=+48.485 (MeOH, c=0.033 g/100 mL)) as colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.63 (d, J=8.0 Hz, 2H), 7.53 (d,J=8.0 Hz, 2H), 4.51-4.44 (m, 1H), 3.57 (d, J=6.4 Hz, 1H), 3.29-3.23 (m,1H), 3.19 (d, J=10.8 Hz, 1H), 3.01 (dd, J=8.8, 17.2 Hz, 1H), 2.85 (d,J=11.2 Hz, 1H), 2.02 (t, J=11.2 Hz, 1H), 1.93 (t, J=11.2 Hz, 1H),1.88-1.81 (m, 1H) 1.56-1.48 (m, 2H), 1.42 (d, J=6.8 Hz, 3H), 1.39-1.26(m, 2H); ES-LCMS m/z 405.0 [M+H]⁺. Peak 2 was concentrated under reducedpressure and then separated by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30 mm, 5 um); mobile phase: [0.1% NH₃:H₂O-MeOH]; B %: 15%-15%) toyield peak 3 and peak 4. Peak 4 was concentrated under reduced pressureto yield a residue which was dissolved in MeCN (15 mL) and water (15 mL)and lyophilized to yield(5R)-3-bromo-5-[1-[(]R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(40.05 mg, 98.8 μmol, 16.0% yield, 100.0% purity, SFC: R_(t)=2.663,Dr=99.64%, [α]^(26.8) _(D)=−83.33 (MeOH, c=0.024 g/100 mL)) as colorlessoil. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.62 (d, J=8.0 Hz, 2H), 7.52 (d,J=8.4 Hz, 2H), 4.51-4.44 (m, 1H), 3.57-3.51 (m, 1H), 3.29-3.23 (m, 1H),3.16 (d, J=12.0 Hz, 1H), 3.02 (dd, J=8.8, 17.2 Hz, 1H), 2.84 (d, J=9.6Hz, 1H), 2.05-1.96 (m, 1H), 1.93-1.83 (m, 1H), 1.77-1.69 (m, 1H),1.66-1.59 (m, 1H), 1.58-1.47 (m, 1H), 1.47-1.37 (m, 4H), 1.32-1.21 (m,1H); ES-LCMS m/z 405.0 [M+H]⁺.

I-154 & I-155

Step 1: tert-Butyl (3S)-3-formylpyrrolidine-1-carboxylate

To a mixture of tert-butyl(3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.7 g, 8.45 mmol, 1 eq)in DCM (50 mL) was added Dess-Martin periodinane (4.66 g, 10.98 mmol,1.3 eq) at 25° C. The mixture was stirred at 25° C. for 12 h. TLC(PE/EtOAc=3/1, R_(f)=0.30) showed the starting material was consumedcompletely. The reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 4/1,TLC: PE/EtOAc=3/1, R_(f)=0.50) to yield tert-butyl(3S)-3-formylpyrrolidine-1-carboxylate (1.5 g, 7.53 mmol, 89.1% yield,N/A purity) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.70 (d,J=1.5 Hz, 1H), 3.80-3.66 (m, 1H), 3.60-3.54 (m, 1H), 3.46-3.36 (m, 2H),3.12-3.03 (m, 1H), 2.20-2.14 (m, 2H), 1.47 (s, 9H).

Step 2: tert-Butyl (3R)-3-vinylpyrrolidine-1-carboxylate

To a solution of methyl(triphenyl)phosphonium; bromide (4.03 g, 11.29mmol, 1.5 eq) in THE (40 mL) was added n-BuLi (2.5 M, 5.42 mL, 1.8 eq)dropwise under N₂ atmosphere at −70° C. The mixture was stirred at−70-0° C. for 0.5 h. The mixture was cooled to −70° C. A solution oftert-butyl (3S)-3-formylpyrrolidine-1-carboxylate (1.5 g, 7.53 mmol, 1eq) in THE (10 mL) was added dropwise under N₂ atmosphere at −70° C. Themixture was stirred at 25° C. for 11.5 h. TLC (PE/EtOAc=3/1, R_(f)=0.60)showed the starting material was consumed completely. The reactionmixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3).The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from PE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=3/1,R_(f)=0.60) to yield tert-butyl (3R)-3-vinylpyrrolidine-1-carboxylate(530 mg, 2.69 mmol, 35.7% yield, N/A purity) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 5.77 (td, J=8.5, 17.1 Hz, 1H), 5.14-5.08 (m, 1H),5.06-5.01 (m, 1H), 3.63-3.40 (m, 2H), 3.35-3.23 (m, 1H), 3.13-2.98 (m,1H), 2.87-2.73 (m, 1H), 2.04-1.96 (m, 1H), 1.79-1.68 (m, 1H), 1.46 (s,9H).

Step 3: tert-Butyl(3S)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate

A mixture of tert-butyl (3R)-3-vinylpyrrolidine-1-carboxylate (530 mg,2.69 mmol, 1 eq), dibromomethanone oxime (600 mg, 2.96 mmol, 1.1 eq) andNaHCO₃ (2.26 g, 26.87 mmol, 10 eq) in EtOAc (20 mL) was stirred at 25°C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.32, 0.27) showed the startingmaterial was consumed completely. The reaction mixture was diluted withH₂O (50 mL) and extracted with EtOAc (50 mL×3). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=3/1, R_(f)=0.32, 027) toyield tert-butyl(3S)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (630mg, 1.97 mmol, 73.5% yield, 100.0% purity) as colorless oil. ¹H NMR (400MHz, CDCl₃) δ ppm 4.73-4.48 (m, 1H), 3.70-3.42 (m, 2H), 3.31 (dd,J=10.5, 17.1 Hz, 2H), 3.24-3.02 (m, 1H), 2.95 (dd, J=8.3, 16.9 Hz, 1H),2.46 (qd, J=7.9, 16.0 Hz, 1H), 2.12-2.02 (m, 1H) 2.00-1.74 (m, 1H), 1.47(s, 9H); ES-LCMS m/z 263.1, 2651 [M-t-Bu+H]⁺.

Step 4: 3-Bromo-5-[(3S)-pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3S)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (300mg, 939.87 μmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol,2 mL, 28.74 eq) at 25° C. The mixture was stirred at 25° C. for 1 h. Thereaction mixture was concentrated under reduced pressure to yield3-bromo-5-[(3S)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (310 mg, 930.65μmol, 99.0% yield, N/A purity, TFA) as colorless oil, which was used inthe next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 4.90-4.69 (m, 1H), 3.62-3.52 (m, 2H), 3.44 (dd, J=10.6, 16.4 Hz,2H), 3.34-3.24 (m, 1H), 2.99 (dd, J=7.6, 17.4 Hz, 1H), 2.80-2.70 (m,1H), 2.34-2.24 (m, 1H), 1.96 (d, J=5.9 Hz, 1H).

Step 5:(5R)-3-Bromo-5-[(3S)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[(3S)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole

A mixture of 3-bromo-5-[(3S)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (310mg, 930.65 μmol, 1 eq, TFA), 1-(bromomethyl)-4-(trifluoromethyl)benzene(225 mg, 941.30 μmol, 1.01 eq) and DIEA (600 mg, 4.64 mmol, 808.63 μL,4.99 eq) in DCM (20 mL) was stirred at 25° C. for 12 h. The reactionmixture was concentrated under reduced pressure to yield a residue whichwas purified by flash silica gel chromatography (from PE/EtOAc=100/1 to1/1, TLC: PE/EtOAc=1/1, R_(f)=0.40). The desired fraction wasconcentrated under reduced pressure to yield a residue (98 mg) which wasseparated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10um); mobile phase: [0.1% NH₃.H₂O/EtOH]; B %: 20%-20%) to yield peak 1and peak 2. Peak 1 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (15 mL) and water (15 mL) andlyophilized to yield(5R)-3-bromo-5-[(3S)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(29.45 mg, 77.84 μmol, 8.4% yield, 99.7% purity, SFC: R_(t)=0.682,Dr=100%, [α]^(27.3) _(D)=+64.41 (CHCl₃, c=0.059 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.58 (d, J=7.8 Hz, 2H), 7.44 (d,J=7.8 Hz, 2H), 4.68 (ddd, J=6.5, 8.9, 10.5 Hz, 1H), 3.72-3.61 (m, 2H),3.27-3.18 (m, 1H), 3.13-3.04 (m, 1H), 2.69 (dt, J=5.3, 8.5 Hz, 1H), 2.57(d, J=7.4 Hz, 3H), 2.43-2.36 (m, 1H), 2.11-1.99 (m, 1H), 1.73-1.63 (m,1H); ES-LCMS m/z 377.1, 379.1 [M+H]⁺. Peak 2 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (15 mL)and water (15 mL) and lyophilized to yield(5S)-3-bromo-5-[(3S)-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(40.43 mg, 105.80 μmol, 11.4% yield, 98.7% purity, SFC: R_(t)=1.338,Dr=100%, [α]^(27.4) _(D)=−61.29 (CHCl₃, c=0.062 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.58 (d, J=7.8 Hz, 2H), 7.44 (d,J=8.2 Hz, 2H), 4.67 (td, J=8.4, 10.2 Hz, 1H), 3.72-3.60 (m, 2H), 3.26(dd, J=10.2, 17.2 Hz, 1H), 2.95 (dd, J=8.2, 17.2 Hz, 1H), 2.73-2.61 (m,2H), 2.60-2.43 (m, 3H), 2.06-1.95 (m, 1H), 1.49 (qd, J=6.7, 13.5 Hz,1H); ES-LCMS m/z 377.1, 379.1 [M+H]⁺.

I-70

Step 1: 4-[4-(Trifluoromethyl)phenoxy]cyclohexanamine

To a stirred solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate(500 mg, 2.32 mmol, 1 eq) in DMF (6 mL) was added NaH (139.33 mg, 3.48mmol, 60% purity, 1.5 eq). The reaction mixture was stirred at 30° C.for 30 min. 1-Fluoro-4-(trifluoromethyl)benzene (381.12 mg, 2.32 mmol,295.44 μL, 1 eq) was added to the above reaction mixture then stirred at80° C. for 12 h. TLC (DCM/MeOH=10:1, R_(f)=0.96) showed startingmaterial was remained and one new spot was detected. The mixture wasevaporated to yield a residue which was purified by flash silica gelchromatography (from DCM/MeOH=1/0 to 10/1, TLC: DCM/MeOH=10/1,R_(f)=0.1) to yield 4-[4-(trifluoromethyl)phenoxy]cyclohexanamine (180mg, 451.27 μmol, 19.4% yield, 65% purity) as yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.93 (d, J=17.4 Hz, 2H), 7.68-7.61 (m, 2H), 7.13 (d,J=8.6 Hz, 2H), 3.72 (s, 1H), 3.06-2.95 (m, 1H), 1.75-1.72 (m, 1H), 1.68(d, J=8.8 Hz, 2H), 1.61 (d, J=10.0 Hz, 3H), 1.42-1.35 (m, 2H); ES-LCMSm/z 260.3 [M+H]⁺.

Step 2: N-[4-[4-(Trifluoromethyl)phenoxy]cyclohexyl]prop-2-enamide

To a solution of 4-[4-(trifluoromethyl)phenoxy]cyclohexanamine (180 mg,451.27 μmol, 1 eq) in THE (8 mL) was added Et₃N (136.99 mg, 1.35 mmol,188.43 μL, 3 eq) and prop-2-enoyl chloride (61.27 mg, 676.91 μmol, 55.19μL, 1.5 eq). The mixture was stirred at 25° C. for 1 h. The reactionmixture was quenched by addition of water (50 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toyield a residue which was purified by preparative HPLC (column: WelchXtimate C18 150*25 mm*5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 38%-68%, 10 min). The desired fraction was lyophilized to yieldN-[4-[4-(trifluoromethyl)phenoxy]cyclohexyl]prop-2-enamide (20 mg, 63.1μmol, 14.0% yield, 98.8% purity) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.05 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.12 (d,J=8.6 Hz, 2H), 6.29-6.19 (m, 1H), 6.11-6.03 (m, 1H), 5.60-5.52 (m, 1H),4.65 (s, 1H), 3.85-3.73 (m, 1H), 1.90 (dd, J=4.4, 13.4 Hz, 2H),1.76-1.68 (m, 2H), 1.63 (d, J=4.6 Hz, 2H), 1.61-1.52 (m, 2H); ES-LCMSm/z 314.1 [M+H]⁺.

I-133 & I-134

Step 1: 2-Bromo-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine

To a solution of 2-bromo-5-methyl-pyridin-4-amine (450 mg, 2.41 mmol, 1eq) in DCM (15 mL) was added DIEA (932.85 mg, 7.22 mmol, 1.26 mL, 3 eq),[3-(trifluoromethyl)phenyl]boronic acid (1.14 g, 6.01 mmol, 2.5 eq),Cu(OAc)₂ (874.00 mg, 4.81 mmol, 2 eq). The mixture was stirred at 25° C.for 72 h under oxygen atmosphere. The reaction mixture was quenched byaddition of water (50 mL), extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.45) to yield2-bromo-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine (200 mg,600.97 μmol, 25.0% yield, 99.5% purity) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.36 (s, 1H), 7.97 (s, 1H), 7.65-7.60 (m, 1H),7.60-7.56 (m, 1H), 7.55 (s, 1H), 7.45 (d, J=7.1 Hz, 1H), 6.99 (s, 1H),2.17 (s, 3H); ES-LCMS m/z 331.0, 333.0 [M+H]⁺.

Step 2: 5-Methyl-N-[3-(trifluoromethyl)phenyl]-2-vinyl-pyridin-4-amine

To a solution of2-bromo-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine (100 mg,302.00 μmol, 1 eq) in 1,4-dioxane (3 mL) and water (1 mL) was addedCs₂CO₃ (295.19 mg, 905.99 μmol, 3 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (55.81 mg, 362.39 μmol,61.47 μL, 1.2 eq) and Pd(dppf)Cl₂ (22.10 mg, 30.20 μmol, 0.1 eq). Themixture was bubbled with N₂ for 2 min and stirred at 100° C. for 30 hunder microwave. The reaction mixture was quenched by addition of water(50 mL), extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 3/1,TLC: PE/EtOAc=3/1, R_(f)=0.49) to yield5-methyl-N-[3-(trifluoromethyl)phenyl]-2-vinyl-pyridin-4-amine (84 mg,301.86 μmol, 99.9% yield, 100% purity) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.26 (s, 1H), 7.53-7.47 (m, 1H), 7.43 (s, 1H), 7.38 (d,J=7.8 Hz, 2H), 7.05 (s, 1H), 6.68 (dd, J=10.8, 17.4 Hz, 1H), 6.06 (dd,J=1.1, 17.5 Hz, 1H), 5.81 (s, 1H), 5.39 (dd, J=1.0, 10.8 Hz, 1H), 2.25(s, 3H); ES-LCMS m/z 279.1 [M+H]⁺.

Step 3:2-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine&2-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine

To a solution of5-methyl-N-[3-(trifluoromethyl)phenyl]-2-vinyl-pyridin-4-amine (84 mg,301.86 μmol, 1 eq) in EtOAc (4 mL) was added NaHCO₃ (253.58 mg, 3.02mmol, 10 eq) and dibromomethanone oxime (73.47 mg, 362.24 μmol, 1.2 eq).The mixture was stirred at 25° C. for 12 h. The reaction mixture wasquenched by addition of water (50 mL), extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=1/0 to 1/1, TLC: PE/EtOAc=1/1, R_(f)=0.55) to yield thecompound which was separated by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O IPA]; B %: 20%-20%, min) toyield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressureto yield a residue which was lyophilized to yield2-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine(15.22 mg, 36.74 μmol, 12.2% yield, 96.6% purity, SFC: R_(t)=3.287 min,ee=99.32%, [α]^(24.8) _(D)=−243.14, MeOH, c=0.051 g/100 mL) as a greensolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (s, 1H), 8.21 (s, 1H),7.60-7.55 (m, 1H), 7.54-7.48 (m, 2H), 7.37 (d, J=7.3 Hz, 1H), 7.10 (s,1H), 5.63-5.56 (m, 1H), 3.73-3.63 (m, 1H), 3.59-3.51 (m, 1H), 3.59-3.50(m, 1H), 2.22 (s, 3H); ES-LCMS m/z 399.9, 401.8 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which waslyophilized to yield2-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-5-methyl-N-[3-(trifluoromethyl)phenyl]pyridin-4-amine(17.75 mg, 43.02 μmol, 14.3% yield, 97% purity, SFC: R_(t)=3.645 min,ee=98.52%, [α]^(24.8) _(D)=+240.68, MeOH, c=0.059 g/100 mL) as a greensolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (s, 1H), 8.21 (s, 1H),7.60-7.55 (m, 1H), 7.54-7.48 (m, 2H), 7.37 (d, J=7.3 Hz, 1H), 7.10 (s,1H), 5.60 (dd, J=7.8, 10.8 Hz, 1H), 3.72-3.63 (m, 1H), 3.59-3.50 (m,1H), 2.22 (s, 3H); ES-LCMS m/z 399.9, 401.8 [M+H]⁺.

I-71

Step 1:N-[(3R)-1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]prop-2-enamide

The starting material was separated by SFC (column: DAICEL CHIRALPAKAD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃.H₂O EtOH]; B %:15%-15%, min) to yield peak 1 (R_(t)=2.697) and peak 2 (R_(t)=3.182).Peak 1 was second separated by SFC (column: DAICEL CHIRALCEL OD-H (250mm*30 mm, 5 μm); mobile phase: [0.1% NH₃.H₂O EtOH]; B %: 20%-20%, min)to yield peak 1. Peak 1 was concentrated under reduced pressure to yielda residue which was dissolved in MeCN (15 mL) and H₂O (10 mL) andlyophilized to yieldN-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]prop-2-enamide(19.41 mg, 53.38 μmol, 10.3% yield, 99.1% purity) (SFC: R_(t)=2.697,ee=100%, [α]^(27.6) _(D)=+65.384 (MeOH, c=0.052 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.56-7.48 (m, 2H), 7.46-7.41 (m,2H), 7.11-7.02 (m, 2H), 6.74-6.68 (m, 1H), 6.57 (d, J=8.6 Hz, 1H), 6.28(dd, J=1.2, 16.8 Hz, 1H), 6.08-5.99 (m, 1H), 5.84 (d, J=7.8 Hz, 1H),5.65 (dd, J=1.6, 10.2 Hz, 1H), 4.67-4.60 (m, 1H), 4.59-4.48 (m, 2H),3.59 (dd, J=2.3, 11.7 Hz, 1H), 3.41-3.34 (m, 1H), 3.22 (dd, J=4.7, 16.4Hz, 1H), 2.82 (d, J=16.0 Hz, 1H); ES-LCMS m/z 361.2 [M+H]⁺.

I-156 & I-157

Step 1: tert-Butyl3-bromo-1-oxa-2,9-diazaspiro[4.5]dec-2-ene-9-carboxylate

A mixture of tert-butyl 3-methylenepiperidine-1-carboxylate (1 g, 5.07mmol, 1 eq), dibromomethanone oxime (1.54 g, 7.60 mmol, 1.5 eq), NaHCO₃(4.26 g, 50.69 mmol, 10 eq) in EtOAc (10 mL) was degassed and purgedwith N₂ for 3 times. The mixture was stirred under N₂ atmosphere at 25°C. for 16 h. The mixture was concentrated, diluted with water (80 mL)and extracted with DCM (50 mL×3). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedto yield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=3/1, R_(f)=0.44) to yieldtert-butyl 3-bromo-1-oxa-2,9-diazaspiro[4.5]dec-2-ene-9-carboxylate (940mg, 2.06 mmol, 40.7% yield, 70.0% purity) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 3.72-3.59 (m, 2H), 3.23-2.94 (m, 4H), 1.97-1.78 (m,4H), 1.46 (s, 9H); ES-LCMS m/z 319.1, 321.1 [M+H]⁺.

Step 2: 3-Bromo-1-oxa-2,9-diazaspiro[4.5]dec-2-ene

A mixture of tert-butyl3-bromo-1-oxa-2,9-diazaspiro[4.5]dec-2-ene-9-carboxylate (940 mg, 2.06mmol, 1 eq), TFA (4.62 g, 40.52 mmol, 3 mL, 19.66 eq) in DCM (15 mL) wasdegassed and purged with N₂ for 3 times. The mixture was stirred underN₂ atmosphere at 25° C. for 2 h. The reaction mixture was concentratedto yield 3-bromo-1-oxa-2,9-diazaspiro[4.5]dec-2-ene (1.37 g, 1.32 mmol,63.8% yield, 32.0% purity, TFA) as yellow oil, which used in the nextstep without further purification. ¹H NMR (400 MHz, CD₃OD) δ ppm3.27-3.11 (m, 4H), 3.08-2.96 (m, 2H), 1.97-1.81 (m, 4H); ES-LCMS m z Nomass found.

Step 3: (S)3-Bromo-9-[[4-(trifluoromethyl)phenyl]methyl]-1-oxa-2,9-diazaspiro[4.5]dec-2-eneand (R)3-bromo-9-[[4-(trifluoromethyl)phenyl]methyl]-1-oxa-2,9-diazaspiro[4.5]dec-2-ene

A mixture of 3-bromo-1-oxa-2,9-diazaspiro[4.5]dec-2-ene (500 mg, 480.33μmol, 1 eq), 1-(bromomethyl)-4-(trifluoromethyl)benzene (114.82 mg,480.33 μmol, 74.07 μL, 1 eq) and DIEA (248.32 mg, 1.92 mmol, 334.66 μL,4 eq) in DCM (5 mL) was degassed and purged with N₂ for 3 times. Themixture was stirred under N₂ atmosphere at 25° C. for 12 h. The reactionmixture was concentrated to yield a residue which was purified bypreparative TLC (PE/EtOAc=5/1, R_(f)=0.45) and then separated by SFC(column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um); mobile phase: [0.1%NH₃H₂O EtOH]; B %: 10%-10%) to yield peak 1 and peak 2. Peak 1 wasconcentrated under reduced pressure to yield a residue which wasdissolved in CH₃CN (10 mL) and water (20 mL), followed by lyophilizationto yield (R)3-bromo-9-[[4-(trifluoromethyl)phenyl]methyl]-1-oxa-2,9-diazaspiro[4.5]dec-2-ene(9.27 mg, 24.38 μmol, 5.1% yield, 99.2% purity, R_(t)=2.163, ee=96.8%,[α]^(24.0) _(D)=+22.857 (MeOH, c=0.035 g/100 mL)) as a white solid. ¹HNMR (500 MHz, CD₃OD) δ ppm 7.63 (d, J=8.2 Hz, 2H), 7.54 (d, J=7.9 Hz,2H), 3.69-3.58 (m, 2H), 3.25-3.16 (m, 1H), 3.12-3.01 (m, 1H), 2.55 (d,J=10.8 Hz, 2H), 2.43-2.18 (m, 2H), 1.86-1.68 (m, 3H), 1.63-1.54 (m, 1H);ES-LCMS m/z 377.1, 379.1 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was purified by preparative HPLC(column: YMC-Actus Triart C18 150*30 mm*5 um; mobile phase: [water(0.225% FA)-ACN]; B %: 23%-48%, 11 min) and lyophilized. The residue wasdissolved in water (20 mL), adjusted to pH=10 with saturated NaHCO₃solution and extracted with DCM (20 mL×2). The organic layer was driedover Na₂SO₄, concentrated to yield a residue which was dissolved inCH₃CN (10 mL) and water (20 mL), followed by lyophilization to yield (S)3-bromo-9-[[4-(trifluoromethyl)phenyl]methyl]-1-oxa-2,9-diazaspiro[4.5]dec-2-ene(7.32 mg, 19.41 μmol, 4.0% yield, 100.0% purity, R_(t)=2.313, ee=91.4%,[α]^(24.0) _(D)=−56 (MeOH, c=0.05 g/100 mL)) as a white solid. ¹H NMR(400 MHz, CD₃OD) δ ppm 7.58 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H),3.59 (s, 2H), 3.19 (d, J=17.2 Hz, 1H), 2.96 (d, J=17.2 Hz, 1H),2.71-2.55 (m, 2H), 2.30 (d, J=11.3 Hz, 1H), 2.14 (t, J=10.2 Hz, 1H),1.88-1.68 (m, 3H), 1.55-1.49 (m, 1H); ES-LCMS m/z 376.8, 378.8 [M+H]⁺.

I-135 & I-136

Step 1: 2-tert-Butyl-5-nitro-aniline

To a solution of 2-tert-butylaniline (2 g, 13.40 mmol, 2.09 mL, 1 eq) inH₂SO₄ (20 mL) was added KNO₃ (2.03 g, 20.10 mmol, 1.5 eq) at 0° C. Themixture was stirred at 0° C. for 5 min. TLC (PE/EtOAc=5/1, R_(f)=0.29)indicated most of the starting material was consumed and one new spotformed. The reaction mixture was quenched by addition of water (50 mL),extracted with EtOAc (50 mL×3). The organic layer was washed with brine(20 mL), dried over Na₂SO₄, filtered, concentrated to yield a residuewhich was purified by flash silica gel chromatography (from PE/EtOAc=1/0to 5/1, TLC: PE/EtOAc=5/1, R_(f)=0.29) to yield2-tert-butyl-5-nitro-aniline (2.15 g, 10.76 mmol, 80.2% yield, 97.2%purity) as yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.22-1.27 (m, 9H)3.91-3.99 (m, 2H) 7.14 (d, J=8.70 Hz, 1H) 7.33 (d, J=2.44 Hz, 1H) 7.34(d, J=2.44 Hz, 1H); ES-LCMS m/z 195.0 [M+H]⁺.

Step 2: 2-tert-Butyl-5-nitro-N-[3-(trifluoromethyl)phenyl]aniline

A mixture of 2-tert-butyl-5-nitro-aniline (2.15 g, 10.01 mmol, 1 eq),1-iodo-3-(trifluoromethyl)benzene (4.08 g, 15.01 mmol, 2.16 mL, 1.5 eq)and t-BuONa (2.89 g, 30.03 mmol, 3 eq) in toluene (40 mL) was addedPd₂(dba)₃ (916.52 mg, 1.00 mmol, 0.1 eq) and XPhos (1.43 g, 3.00 mmol,0.3 eq), degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 110° C. for 12 h under N₂ atmosphere. The reactionmixture was quenched by addition of water (50 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered, concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 5/1,TLC: PE/EtOAc=5/1, R_(f)=0.53) to yield2-tert-butyl-5-nitro-N-[3-(trifluoromethyl)phenyl]aniline (3.88 g, 8.65mmol, 86.4% yield, 75.4% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.49 (s, 9H) 7.05 (d, J=7.83 Hz, 1H) 7.10 (s, 1H) 7.19 (d, J=7.83Hz, 1H) 7.36-7.42 (m, 1H) 7.59 (d, J=9.00 Hz, 1H) 7.89 (dd, J=8.61, 2.35Hz, 1H) 8.08 (d, J=2.74 Hz, 1H); ES-LCMS m/z 339.2 [M+H]⁺.

Step 3: 4-tert-Butyl-N3-[3-(trifluoromethyl)phenyl]benzene-1,3-diamine

To a solution of2-tert-butyl-5-nitro-N-[3-(trifluoromethyl)phenyl]aniline (3.88 g, 8.60mmol, 1 eq) in EtOH (15 mL), H₂O (10 mL) and THE (15 mL), was added Fe(2.40 g, 43.01 mmol, 5 eq) and NH₄Cl (4.60 g, 86.01 mmol, 10 eq). Themixture was stirred at 70° C. for 3 h under N₂ atmosphere. TLC(PE/EtOAc=5/1 R_(f)=0.55) indicated most of the starting material wasconsumed and one new spot formed. The mixture was filtered, and thefilter cake was rinsed with PE (10 mL×2), dried. Then the reactionmixture was quenched by addition of water (50 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered, concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 5/1,TLC: PE/EtOAc=5/1, R_(f)=0.55) to yield4-tert-butyl-N3-[3-(trifluoromethyl)phenyl]benzene-1,3-diamine (2.7 g,7.01 mmol, 81.4% yield, 80.0% purity) as yellow oil. ¹H NMR (500 MHz,CDCl₃) δ ppm 1.59-1.68 (m, 9H) 3.83 (s, 1H) 3.74-3.91 (m, 1H) 5.76 (s,1H) 6.75 (dd, J=8.54, 2.29 Hz, 1H) 6.85 (d, J=2.14 Hz, 1H) 7.18 (d,J=8.39 Hz, 1H) 7.29 (s, 1H) 7.47-7.55 (m, 2H); ES-LCMS m/z 309.3 [M+H]⁺.

Step 4: 2-tert-Butyl-5-iodo-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of4-tert-butyl-N3-[3-(trifluoromethyl)phenyl]benzene-1,3-diamine (1.2 g,3.11 mmol, 1 eq) in MeCN (15 mL) cooled to 0° C. was added H₂SO₄ (763.40mg, 7.78 mmol, 414.89 μL, 2.5 eq) dissolved in H₂O (5 mL). Afterstirring for 5 min, a solution of NaNO₂ (429.63 mg, 6.23 mmol, 2 eq) inH₂O (5 mL) was added dropwise and the reaction mixture was stirred foran additional 15 min at 0° C. Then a solution of NaI (1.87 g, 12.45mmol, 4 eq) in H₂O (5 mL) was added. The mixture was stirred at 60° C.for 1 h. The reaction mixture was quenched by addition of water (50 mL),extracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered. Then The residue waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 5/1,TLC: PE/EtOAc=5/1, R_(f)=0.63) to yield2-tert-butyl-5-iodo-N-[3-(trifluoromethyl)phenyl]aniline (460 mg, 877.82μmol, 28.1% yield, 80% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δppm 1.40 (s, 9H) 5.48 (s, 1H) 6.90-6.94 (m, 1H) 7.00 (s, 1H) 7.09 (d,J=7.43 Hz, 1H) 7.16 (d, J=8.22 Hz, 1H) 7.31 (t, J=7.83 Hz, 1H) 7.44 (dd,J=8.61, 1.96 Hz, 1H) 7.54-7.58 (m, 1H); ES-LCMS m/z 420.1 [M+H]⁺.

Step 5: 2-tert-Butyl-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline

To a solution of2-tert-butyl-5-iodo-N-[3-(trifluoromethyl)phenyl]aniline (410 mg, 782.40μmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (156.65 mg,1.02 mmol, 172.52 μL, 1.3 eq) in 1,4-dioxane (2.5 mL) and H₂O (0.5 mL)was added Pd(dppf)Cl₂ (28.62 mg, 39.12 μmol, 0.05 eq) and Cs₂CO₃ (509.84mg, 1.56 mmol, 2 eq). The mixture was stirred at 80° C. for 2 h under N₂atmosphere. The reaction mixture was quenched by addition of water (50mL), extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered. Then the residuewas purified by flash silica gel chromatography (from PE/EtOAc=1/0 to10/1, TLC: PE/EtOAc=10/1, R_(f)=0.61) to yield2-tert-butyl-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline (310 mg,776.55 μmol, 99.2% yield, 80.0% purity) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.35-1.43 (m, 9H) 5.12-5.29 (m, 1H) 5.44-5.53 (m, 1H) 5.64(dd, J=17.61, 0.73 Hz, 1H) 6.54-6.71 (m, 1H) 6.84-6.92 (m, 1H) 6.96-7.08(m, 2H) 7.12-7.20 (m, 1H) 7.23-7.32 (m, 2H) 7.38-7.44 (m, 1H); ES-LCMSm/z 320.3 [M+H]⁺.

Step 6:5-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-tert-butyl-N-[3-(trifluoromethyl)phenyl]aniline&5-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-tert-butyl-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of2-tert-butyl-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline (280 mg,701.40 μmol, 1 eq), dibromomethanone oxime (184.95 mg, 911.81 μmol, 1.3eq) in EtOAc (20 mL) was added NaHCO₃ (589.22 mg, 7.01 mmol, 10 eq). Themixture was stirred at 25° C. for 3 h under N₂ atmosphere. The reactionmixture was quenched by addition of water (50 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 5/1, TLC: PE/EtOAc=5/1, R_(f)=0.54)to yield a product. The residue was separated by SFC (column: DAICELCHIRALCEL OJ-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃.H₂O ETOH];B %: 20%-20%, min. Peak 1, 1.905, Peak 2, 2.186) to yield peak 1 (1.930)and peak 2 (2.207)). Peak 1 was concentrated under reduced pressure toyield a residue which was dissolved in MeCN (20 mL) and H₂O (10 mL) andlyophilized to yield5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-tert-butyl-N-[3-(trifluoromethyl)phenyl]aniline(45.7 mg, 101.49 μmol, 14.4% yield, 98.0% purity) (SFC: R_(t)=1.930,ee=100%, [α]^(25.7) _(D)=−130.9 (MeOH, c=0.050 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.42 (s, 9H) 3.18 (dd, J=17.17,8.93 Hz, 1H) 3.58 (dd, J=17.09, 10.83 Hz, 1H) 5.55 (s, 1H) 5.60 (dd,J=10.68, 9.16 Hz, 1H) 6.89-6.93 (m, 1H) 6.99 (s, 1H) 7.07 (d, J=7.78 Hz,1H) 7.11 (dd, J=8.32, 1.91 Hz, 1H) 7.21-7.25 (m, 1H) 7.30 (t, J=7.86 Hz,1H) 7.48 (d, J=8.24 Hz, 1H); ES-LCMS m/z 441.0, 443.0 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (10 mL) and lyophilized to yield5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-tert-butyl-N-[3-(trifluoromethyl)phenyl]aniline(44.57 mg, 97.06 μmol, 13.8% yield, 96.1% purity) (SFC: R_(t)=2.207,ee=99.94%, [α]^(25.7) _(D)=+120.0 (MeOH, c=0.055 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.38-1.45 (m, 9H) 3.18 (dd,J=17.17, 8.93 Hz, 1H) 3.58 (dd, J=17.09, 10.83 Hz, 1H) 5.54 (s, 1H) 5.60(dd, J=10.68, 9.16 Hz, 1H) 6.91 (d, J=8.09 Hz, 1H) 6.99 (s, 1H) 7.07 (d,J=7.78 Hz, 1H) 7.11 (dd, J=8.24, 1.83 Hz, 1H) 7.23 (d, J=1.68 Hz, 1H)7.30 (t, J=8.01 Hz, 1H) 7.48 (d, J=8.24 Hz, 1H); ES-LCMS m/z 441.0,443.0 [M+H]⁺.

I-137 & I-138

Step 1: 4-Amino-3-isopropenyl-N-methyl-benzenesulfonamide

To a solution of 4-amino-3-bromo-N-methyl-benzenesulfonamide (1 g, 2.68mmol, 1 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(540.01 mg, 3.21 mmol, 1.2 eq) in 1,4-dioxane (6 mL) and H₂O (2 mL) wasadded Cs₂CO₃ (2.62 g, 8.03 mmol, 3 eq) and Pd(dppf)Cl₂ (195.95 mg,267.80 μmol, 0.1 eq). The mixture was stirred at 25° C. for 3 h under N₂atmosphere. To the mixture was added water (30 mL) and extracted withethyl acetate (30 mL×3). The combined organic phase was washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuum to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.28) to yield 4-amino-3-isopropenyl-N-methyl-benzenesulfonamide(550 mg, 2.21 mmol, 82.6% yield, 91% purity) as yellow oil. ¹H NMR (500MHz, CDCl3) δ ppm 7.57-7.49 (m, 2H), 6.72 (d, J=8.1 Hz, 1H), 5.43-5.36(m, 1H), 5.11 (d, J=0.9 Hz, 1H), 4.31 (s, 2H), 4.23 (s, 1H), 2.65 (d,J=5.5 Hz, 3H), 2.08 (s, 3H); ES-LCMS m/z 226.9 [M+H]⁺.

Step 2:3-Isopropenyl-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide

To a solution of 4-amino-3-isopropenyl-N-methyl-benzenesulfonamide (400mg, 1.61 mmol, 1 eq) and [3-(trifluoromethyl)phenyl]boronic acid (1.53g, 8.04 mmol, 5 eq) in DCM (20 mL) was added Cu(OAc)₂ (350.59 mg, 1.93mmol, 1.2 eq) and DIEA (415.78 mg, 3.22 mmol, 560.35 μL, 2 eq). Themixture was stirred at 25° C. for 12 h under O₂ (15 Psi) atmosphere. Theresulting product was filtered and concentrated in vacuo to yield theresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.31) to yield3-isopropenyl-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(280 mg, 687.93 μmol, 42.8% yield, 91% purity) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.65-7.62 (m, 2H), 7.49-7.44 (m, 1H), 7.39 (s,1H), 7.36-7.31 (m, 2H), 7.31-7.28 (m, 1H), 6.36 (s, 1H), 5.48-5.44 (m,1H), 5.17 (s, 1H), 4.29-4.22 (m, 1H), 2.70 (d, J=5.5 Hz, 3H), 2.11 (s,3H); ES-LCMS m/z 371.2 [M+H]⁺.

Step 3:3-[(5R)-3-Bromo-5-methyl-4H-isoxazol-5-yl]-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide&3-[(5S)-3-bromo-5-methyl-4H-isoxazol-5-yl]-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide

To a solution of3-isopropenyl-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(280 mg, 687.93 μmol, 1 eq) in EtOAc (10 mL) was added NaHCO₃ (577.93mg, 6.88 mmol, 10 eq) and dibromomethanone oxime (167.44 mg, 825.51μmol, 1.2 eq). The mixture was stirred at 25° C. for 12 h. To themixture was added water (30 mL) and extracted with ethyl acetate (30mL×3). The combined organic phase was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.43) to yield theproduct. The product was separated by SFC (column: DAICEL CHIRALCEL OJ-H(250 mm*30 mm, 5 μm); mobile phase: [0.1% NH3-H₂O ETOH]; B %: 20%-20%,min) to yield peak 1 (R_(t)=3.231 min, ee=100%) and peak 2 (R_(t)=3.403min, ee=93.84%). Peak 1 was concentrated under reduced pressure to yielda residue which was dissolved in MeCN (20 mL) and H₂O (40 mL) andlyophilized to yield3-[(5R)-3-bromo-5-methyl-4H-isoxazol-5-yl]-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(40.65 mg, 82.57 μmol, 12.0% yield, 100% purity, SFC: R_(t)=3.231 min,ee=100%, [α]^(25.7) _(D)=−58.065 (MeOH, c=0.062 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.74-7.68 (m, 2H), 7.49-7.43 (m,1H), 7.41-7.35 (m, 2H), 7.33 (d, J=7.0 Hz, 1H), 7.29 (s, 1H), 4.30 (s,1H), 3.77 (d, J=17.2 Hz, 1H), 3.24 (d, J=17.2 Hz, 1H), 2.70 (d, J=5.5Hz, 3H), 1.85 (s, 3H); ES-LCMS m/z 492.0, 494.0 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield3-[(5S)-3-bromo-5-methyl-4H-isoxazol-5-yl]-N-methyl-4-[3-(trifluoromethyl)anilino]benzenesulfonamide(59.40 mg, 120.66 μmol, 17.5% yield, 100% purity, SFC: R_(t)=3.403 min,ee=93.84%, [α]^(25.7) _(D)=+57.143 (MeOH, c=0.056 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.74-7.68 (m, 2H), 7.49-7.43 (m,1H), 7.40-7.35 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 4.30 (s,1H), 3.77 (d, J=17.2 Hz, 1H), 3.24 (d, J=17.2 Hz, 1H), 2.70 (d, J=5.5Hz, 3H), 1.85 (s, 3H); ES-LCMS m/z 492.0, 494.0 [M+H]⁺.

I-45

Step 1: 2-Chloro-5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridine

A mixture of 4-bromo-2-chloro-5-methyl-pyridine (290 mg, 1.40 mmol, 1eq), 3-(trifluoromethyl)phenol (239.08 mg, 1.47 mmol, 177.10 μL, 1.05eq), CuI (26.75 mg, 140.46 μmol, 0.1 eq), K₃PO₄ (298.14 mg, 1.40 mmol, 1eq) and pyridine-2-carboxylic acid (17.29 mg, 140.46 μmol, 0.1 eq) inDMSO (10 mL) was degassed and purged with N₂ for 3 times and then themixture was stirred under N₂ atmosphere at 120° C. for 12 h. TLC(PE/EtOAc=5/1, R_(f)=0.60) indicated starting material was consumedcompletely and one new spot formed. The reaction mixture was quenched byaddition of water (100 mL) and extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine (40 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=1/0 to 10/1, TLC: PE/EtOAc=5/1, R_(f)=0.60) to yield2-chloro-5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridine (300 mg, 907.31μmol, 64.6% yield, 87.0% purity) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.31 (s, 1H), 7.75-7.71 (m, 1H), 7.70-7.67 (m, 1H), 7.63(s, 1H), 7.52 (d, J=8.1 Hz, 1H), 6.72 (s, 1H), 2.25 (s, 3H).

Step 2: 5-Methyl-4-[3-(trifluoromethyl)phenoxy]pyridin-2-amine

A mixture of 2-chloro-5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridine(300 mg, 907.31 μmol, 1 eq), Pd₂(dba)₃ (83.08 mg, 90.73 μmol, 0.1 eq),t-Bu Xphos (77.06 mg, 181.46 μmol, 0.2 eq) and LiHMDS (1 M, 4.54 mL, 5eq) in THE (30 mL) was degassed and purged with N₂ for 3 times and thenthe mixture was stirred under N₂ atmosphere at 80° C. for 12 h. Thereaction mixture was quenched by addition of water (50 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers were washed with brine(40 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue which was purified by flash silica gelchromatography (from PE/EtOAc=3/1 to DCM/MeOH=5/1, TLC: DCM/MeOH=5/1,R_(f)=0.48) to yield5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridin-2-amine (100 mg, 298.25μmol, 32.9% yield, 80.0% purity) as brown oil. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.76 (s, 1H), 7.70-7.66 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.44 (s,1H), 7.40 (d, J=8.2 Hz, 1H), 5.73 (s, 2H), 1.97 (s, 3H); ES-LCMS: m/z269.1 [M+H]⁺.

Step 3:N-[5-Methyl-4-[3-(trifluoromethyl)phenoxy]-2-pyridyl]prop-2-enamide

To a solution of 5-methyl-4-[3-(trifluoromethyl)phenoxy]pyridin-2-amine(100 mg, 298.25 μmol, 1 eq) in DCM (4 mL) was added DIEA (77.09 mg,596.49 μmol, 103.90 μL, 2 eq) and prop-2-enoyl chloride (26.99 mg,298.25 μmol, 24.32 μL, 1 eq). The mixture was stirred at 0° C. for 20min. The reaction mixture was quenched by addition of water (50 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine (40 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue which was purified by flash silicagel chromatography (from PE/EtOAc=1/0 to 3/1, TLC: PE/EtOAc=3/1,R_(f)=0.40) to yieldN-[5-methyl-4-[3-(trifluoromethyl)phenoxy]-2-pyridyl]prop-2-enamide(17.08 mg, 50.44 μmol, 16.9% yield, 95.2% purity) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.15 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H),7.56-7.50 (m, 1H), 7.50-7.44 (m, 1H), 7.33 (s, 1H), 7.28 (s, 1H),6.41-6.35 (m, 1H), 6.23-6.15 (m, 1H), 5.77 (d, J=10.6 Hz, 1H), 2.26 (s,3H); ES-LCMS m/z 323.2 [M+H]⁺.

I-139 & I-140

Step 1: 4-(Benzylamino)-3-bromo-N-methyl-benzenesulfonamide

A mixture of 3-bromo-4-fluoro-N-methyl-benzenesulfonamide (1 g, 3.73mmol, 1 eq) and phenylmethanamine (800 mg, 7.47 mmol, 813.84 μL, 2 eq)in DMSO (15 mL) was stirred at 140° C. for 1 h. TLC (PE/EtOAc=1/1,R_(f)=0.40) showed the starting material was consumed completely. Thereaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(20 mL×3). The combined organic layers dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 1/1,TLC: PE/EtOAc=1/1, R_(f)=0.40) to yield4-(benzylamino)-3-bromo-N-methyl-benzenesulfonamide (600 mg, 1.63 mmol,43.7% yield, 96.5% purity) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δppm 7.94 (d, J=2.0 Hz, 1H), 7.61 (dd, J=2.0, 8.6 Hz, 1H), 7.41-7.28 (m,5H), 6.62 (d, J=8.6 Hz, 1H), 5.32-5.22 (m, 1H), 4.47 (d, J=5.9 Hz, 2H),2.63 (d, J=5.5 Hz, 3H); ES-LCMS m/z 354.8, 356.8 [M+H]⁺.

Step 2: 4-(Benzylamino)-N-methyl-3-vinyl-benzenesulfonamide

To a solution of 4-(benzylamino)-3-bromo-N-methyl-benzenesulfonamide(600 mg, 1.63 mmol, 1 eq) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (544.80 mg, 3.54 mmol,600 μL, 2.17 eq) in 1,4-dioxane (20 mL) and H₂O (4 mL) was addedPd(dppf)Cl₂ (120 mg, 164.00 μmol, 1.01e-1 eq) and Cs₂CO₃ (1.06 g, 3.26mmol, 2 eq). The mixture was stirred under N₂ atmosphere at 100° C. for2 h. TLC (PE/EtOAc=3/1, R_(f)=0.30) showed the starting material wasconsumed completely. The reaction mixture was quenched with H₂O (30 mL)and extracted with EtOAc (30 mL×3). The combined organic layers driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=3/1, R_(f)=0.30) to yield4-(benzylamino)-N-methyl-3-vinyl-benzenesulfonamide (400 mg, 1.19 mmol,73.0% yield, 90.0% purity) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δppm 7.69 (d, J=2.3 Hz, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.36-7.29 (m,4H), 7.24-7.18 (m, 1H), 6.95 (dd, J=11.0, 17.2 Hz, 1H), 6.55 (d, J=8.6Hz, 1H), 5.70 (dd, J=1.6, 17.2 Hz, 1H), 5.39 (dd, J=1.6, 11.0 Hz, 1H),4.47 (s, 2H), 2.45 (s, 3H); ES-LCMS m/z 303.1 [M+H]⁺.

Step 3:4-(Benzylamino)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-benzenesulfonamideand4-(benzylamino)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-benzenesulfonamide

To a solution of 4-(benzylamino)-N-methyl-3-vinyl-benzenesulfonamide(160 mg, 476.20 μmol, 1 eq) in EtOAc (5 mL) was added NaHCO₃ (200 mg,2.38 mmol, 5 eq). The mixture was stirred at 25° C. for 12 h. TLC(PE/EtOAc=3/1, R_(f)=0.37) showed the starting material was consumedcompletely. The reaction mixture was diluted with H₂O (30 mL) andextracted with EtOAc (30 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 36%-66%, 10min). The desired compound was concentrated under reduced pressure toyield a residue which was separated by chiral SFC (column: DAICELCHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O/EtOH]; B%: 35%-35%) to yield peak 1 and peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (10 mL)and water (10 mL) and lyophilized to yield4-(benzylamino)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-benzenesulfonamide(24.59 mg, 57.95 μmol, 12.2% yield, 100.0% purity, SFC: R_(t)=3.649,ee=99.92%, [α]^(28.4) _(D)=−41.935 (MeOH, c=0.062 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.70 (dd, J=2.0, 8.6 Hz, 1H), 7.60(d, J=2.3 Hz, 1H), 7.40-7.27 (m, 5H), 6.78-6.73 (m, 1H), 6.76 (d, J=8.6Hz, 1H), 5.72 (t, J=11.3 Hz, 1H), 5.24-5.14 (m, 1H), 4.48-4.37 (m, 2H),4.20 (d, J=5.1 Hz, 1H), 3.66-3.39 (m, 2H), 2.64 (d, J=5.5 Hz, 3H);ES-LCMS m/z 424.1, 426.1 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (10 mL) andwater (10 mL) and lyophilized to yield4-(benzylamino)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-benzenesulfonamide(37.5 mg, 88.38 μmol, 18.6% yield, 100.0% purity) as a white solid, SFC:R_(t)=3.934, ee=99.30%, [α]^(28.4) _(D)=+42.86 (MeOH, c=0.028 g/100 mL))as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.70 (dd, J=2.3, 8.6 Hz,1H), 7.62-7.62 (m, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.42-7.30 (m, 5H), 6.76(d, J=8.6 Hz, 1H), 5.72 (t, J=11.2 Hz, 1H), 5.24-5.14 (m, 1H), 4.47-4.37(m, 2H), 4.18 (d, J=5.9 Hz, 1H), 3.65-3.42 (m, 2H), 2.64 (d, J=5.5 Hz,3H); ES-LCMS m/z 424.1, 426.1 [M+H]⁺.

I-72

Step 1: tert-butylN-[(1S,5R)-3-prop-2-enoyl-3-azabicyclo[3.1.0]hexan-6-yl]carbamate

To a solution of tert-butylN-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (51 mg, 257.24 μmol,1 eq) and DIEA (99.74 mg, 771.71 μmol, 134.42 μL, 3 eq) in DCM (5 mL)was added a solution of prop-2-enoyl chloride (23.28 mg, 257.24 μmol,20.97 μL, 1 eq) in DCM (1 mL) dropwise at 0° C. and stirred at 0° C. for30 min. TLC (DCM/MeOH=10/1 R_(f)=0.56) showed the starting material wasconsumed and a new spot was formed. The solvent was removed to give aresidue which was purified by preparative TLC (DCM/MeOH=10/1) to yieldtert-butylN-[(1S,5R)-3-prop-2-enoyl-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (52mg, 201.97 μmol, 78.52% yield, 98.0% purity) as colorless gum. ¹H NMR(500 MHz, CDCl₃) δ ppm 6.33 (d, J=6.7 Hz, 2H), 5.71-5.61 (m, 1H), 4.72(br s, 1H), 3.93 (d, J=12.5 Hz, 1H), 3.84 (br s, 1H), 3.67 (dd, J=4.7,10.2 Hz, 1H), 3.53 (dd, J=4.8, 12.6 Hz, 1H), 2.30-2.27 (m, 1H),1.86-1.82 (m, 1H), 1.78-1.70 (m, 1H), 1.44 (s, 9H); ES-LCMS m/z 253.3[M+H]⁺.

Step 2: 1-[(1S,5R)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one

To a solution of tert-butylN-[(1S,5R)-3-prop-2-enoyl-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (52mg, 201.97 μmol, 1 eq) in DCM (1 mL) was added TFA (0.2 mL) and themixture was stirred at 20° C. for 2 h. The solvent was removed and theresidue was adjusted to pH 8 with NH₃.H₂O. The mixture was concentratedto give 1-[(1S,5R)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one(30 mg, crude) as colorless gum

Step 3:1-[(1S,5R)-6-[[3-(Trifluoromethyl)phenyl]methylamino]-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one

To a solution of1-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one (30 mg,crude) in MeOH (5 mL) was added 3-(Trifluoromethyl)benzaldehyde (30.89mg, 177.41 μmol, 1 eq) and the mixture was stirred at 20° C. for 1 h.NaBH₃CN (33.45 mg, 532.22 μmol, 3 eq) was added and the mixture wasstirred at 20° C. for 16 h. The mixture was concentrated by reducedpressure to give a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water (0.04%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 32%-62%, 10 min), followed bylyophilization to yield1-[(1S,5R)-6-[[3-(trifluoromethyl)phenyl]methylamino]-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one(24.28 mg, 77.34 μmol, 43.60% yield, 98.85% purity) as colorless gum. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.56 (s, 1H), 7.52 (d, J=7.3 Hz, 1H),7.49-7.42 (m, 2H), 6.36-6.29 (m, 2H), 5.65 (dd, J=5.3, 7.0 Hz, 1H), 3.87(s, 2H), 3.80 (d, J=12.5 Hz, 1H), 3.65-3.62 (m, 2H), 3.49 (dd, J=4.2,12.6 Hz, 1H), 1.93 (t, J=2.0 Hz, 1H), 1.86 (br s, 1H), 1.69-1.62 (m,2H); ES-LCMS m/z 311.3 [M+H]⁺.

I-73

Step 1: Tert-butyl4-methyl-4-(prop-2-enoylamino)piperidine-1-carboxylate

To a mixture of tert-butyl 4-amino-4-methyl-piperidine-1-carboxylate(200.0 mg, 933.26 μmol, 1 eq) and DIEA (241.23 mg, 1.87 mmol, 325.11 μL,2 eq) in DCM (10 mL) cooled to 0° C. was added prop-2-enoyl chloride(84.47 mg, 933.26 μmol, 76.10 μL, 1 eq) in portion wise at 0° C. Themixture was stirred at 0° C. for 0.5 h. TLC (PE/EtOAc=1/1, R_(f)=0.29)indicated the staring material was remained and one new spot wasdetected. The reaction mixture was concentrated to yield a residue whichwas purified by flash silica gel chromatography (from PE/EtOAc=100/1 to1/1, TLC: PE/EtOAc=1/1, R_(f)=0.29) to yield tert-butyl4-methyl-4-(prop-2-enoylamino)piperidine-1-carboxylate (248.43 mg,786.90 μmol, 84.3% yield, 85.0% purity) as light yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 6.28-6.17 (m, 1H), 6.13-6.01 (m, 1H), 5.59 (dd, J=1.2,10.2 Hz, 1H), 5.41 (s, 1H), 3.63 (s, 2H), 3.18-3.11 (m, 2H), 2.03-2.01(m, 2H), 1.61-1.58 (m, 2H), 1.43 (s, 12H); ES-LCMS m/z 269.3 [M+H]⁺.

Step 2: N-(4-Methyl-4-piperidyl)prop-2-enamide

To a solution of tert-butyl4-methyl-4-(prop-2-enoylamino)piperidine-1-carboxylate (240 mg, 760.20μmol, 1 eq) in DCM (6 mL) was added TFA (1.69 mL) under N₂. The mixturewas stirred at 25° C. for 2 h. TLC (PE/EtOAc=5/1, R_(f)=0.01) indicatedstarting material was consumed completely and one new spot formed. Thereaction mixture was concentrated under reduced pressure to yieldN-(4-methyl-4-piperidyl)prop-2-enamide (150 mg, 713.3 μmol, 93.8% yield,80% purity) as colorless liquid which was used in next step directlywithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.33 (s,1H), 7.95-7.70 (m, 1H), 6.32-6.24 (m, 1H), 6.20-6.11 (m, 1H), 5.78 (d,J=10.6 Hz, 1H), 3.33 (s, 4H), 2.59 (d, J=15.7 Hz, 2H), 1.92 (td, J=7.5,14.4 Hz, 2H), 1.55 (s, 3H).

Step 3:N-[4-Methyl-1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide

To a solution ofN-(4-methyl-4-piperidyl)prop-2-enamide (150 mg, 531.43μmol, 1 eq, TFA) in DCM (8 mL) was added DIEA (274.73 mg, 2.13 mmol,370.25 μL, 4 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (127.03mg, 531.43 μmol, 81.95 μL, 1 eq) under N₂. The mixture was stirred at25° C. for 12 h. The mixture was concentrated and water (80 mL) wasadded. The mixture was extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash silica gelchromatography (From PE/EtOAc=1/0 to 5/1, R_(f)=0.08) to yieldN-[4-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]prop-2-enamide(81.13 mg, 242.63 μmol, 45.6% yield, 97.6% purity) as a light yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.56 (d, J=7.8 Hz, 2H), 7.44 (d,J=7.8 Hz, 2H), 6.27-6.20 (m, 1H), 6.11-6.01 (m, 1H), 5.60 (dd, J=1.6,10.2 Hz, 1H), 5.19 (s, 1H), 3.54 (s, 2H), 2.57 (d, J=11.0 Hz, 2H),2.32-2.20 (m, 2H), 2.16-2.05 (m, 2H), 1.72-1.68 (m, 2H), 1.45 (s, 3H);ES-LCMS m/z 327.3 [M+H]⁺.

I-204 & I-205

Step 1: 3-Bromo-5-(4-piperidyl)-4,5-dihydroisoxazole

To a solution of tert-butyl 4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (250 mg, 675.23 μmol, 1eq) in DCM (5 mL) was added TFA (1.54 g, 1 mL). The mixture was stirredat 25° C. for 2 h. The mixture was concentrated to yield3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (250 mg, 648.18 μmol, 96.0%yield, 90.0% purity, TFA) as yellow oil, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.63-4.49(m, 1H), 3.60 (d, J=11.6 Hz, 2H), 3.31 (dd, J=10.8, 17.2 Hz, 1H),3.10-2.91 (m, 3H), 2.15-2.10 (m, 1H), 2.00-1.81 (m, 2H), 1.77-1.58 (m,2H); ES-LCMS m/z 232.80 [M+H]⁺.

Step 2: [(1S)-1-[4-(Trifluoromethyl)phenyl]ethyl]methanesulfonate

To a solution of (IS)-1-[4-(trifluoromethyl)phenyl]ethanol (200 mg, 1.05mmol, 1 eq) in DCM (20 mL) was added DIEA (407.78 mg, 3.16 mmol, 549.57μL, 3.0 eq) and methanesulfonyl chloride (140 mg, 1.22 mmol, 94.59 μL,1.16 eq) at 0° C. under N₂. The mixture was allowed to warm to roomtemperature (28° C.) with stirred for 1 h under N₂. TLC (PE/EtOAc=6/1,R_(f)=0.5) showed that new point was formed and start material wasconsumed completely. The reaction mixture was quenched by addition ofH₂O (10 mL) and extracted with DCM (10 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield[(IS)-1-[4-(trifluoromethyl)phenyl]ethyl]methanesulfonate (295 mg, 1.04mmol, 99.3% yield, 95.0% purity) as yellow oil, which was used in thenext step without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 5.82-5.76 (m, 1H), 2.86(s, 3H), 1.74 (d, J=6.8 Hz, 3H).

Step 3:3-Bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 3-bromo-5-(4-piperidyl)-4, 5-dihydroisoxazole (250 mg,965.23 μmol, 1 eq) and[(IS)-1-[4-(trifluoromethyl)phenyl]ethyl]methanesulfonate (295 mg, 1.04mmol, 1.08 eq) in DMF (10 mL) was added Cs₂CO₃ (314.49 mg, 965.23 μmol,1 eq). The mixture was stirred at 25° C. for 48 h. The reaction mixturewas quenched by addition of H₂O (20 mL) and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine (30 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue which was purified by preparative HPLC (column: Welch XtimateC18 150*25 mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:52%-82%, 10 min) to yield3-bromo-5-[1-[(]R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(90 mg, 210.98 μmol, 21.9% yield, 95.0% purity) as a white solid.ES-LCMS m/z 407.1 [M+H]⁺.

Step 4:(5S)-3-Bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazoleand(5R)-3-bromo-5-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole

3-Bromo-5-[1-[(JR)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(90 mg, 210.98 mmol, 1 eq) was separated by SFC (column: DAICELCHIRALPAK IG (250 mm*30 mm, 10 mm); mobile phase: [0.1% NH₃H₂O MeOH]; B%: 20%-20%, min) to yield peak 1 and peak 2. Peak 2 was concentratedunder reduced pressure to give a residue which was dissolved in MeCN (15mL) and water (15 mL) and lyophilized to yield(5R)-3-bromo-5-[1-[(JR)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(21.63 mg, 52.89 μmol, 25.1% yield, 99.1% purity, SFC: R_(t)=2.861,Dr=99.5%, [α]^(26.8) _(D)=−70.0 (MeOH, c=0.020 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.66 (d, J=7.6 Hz, 2H), 7.56 (d,J=7.6 Hz, 2H), 4.52-4.45 (m, 1H), 3.70 (br s, 1H), 3.30-3.16 (m, 2H),3.02 (dd, J=8.8, 17.2 Hz, 1H), 2.92 (br s, 1H), 2.33-1.93 (m, 2H), 1.88(d, J=12.4 Hz, 1H), 1.56 (s, 2H), 1.47 (d, J=5.6 Hz, 3H), 1.43-1.28 (m,2H); ES-LCMS m/z 405.0 [M+H]⁺. Peak 1 was concentrated under reducedpressure to yield a residue which was separated by SFC (column: DAICELCHIRALPAK AD-H (250 mm*30 mm, 5 mm); mobile phase: [0.1% NH₃H₂O MeOH]; B%: 10%-10%, min) to give peak 1. Peak 1 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (15 mL) andwater (15 mL) and lyophilized to yield(5S)-3-bromo-5-[1-[(JR)-1-[4-(trifluoromethyl)phenyl]ethyl]-4-piperidyl]-4,5-dihydroisoxazole(15.06 mg, 36.68 μmol, 17.4% yield, 98.7% purity, SFC: R_(t)=2.602,Dr=96.76, [α]^(26.9) _(D)=+123.81 (MeOH, c=0.021 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.62 (d, J=8.4 Hz, 2H), 7.52 (d,J=8.4 Hz, 2H), 4.52-4.44 (m, 1H), 3.55 (d, J=5.6 Hz, 1H), 3.29-3.22 (m,1H), 3.17 (d, J=11.2 Hz, 1H), 3.02 (dd, J=8.8, 17.2 Hz, 1H), 2.84 (d,J=12.4 Hz, 1H), 2.01 (t, J=9.2 Hz, 1H), 1.89 (t, J=12.4 Hz, 1H), 1.74(d, J=13.2 Hz, 1H), 1.63 (d, J=12.4 Hz, 1H), 1.55-1.47 (m, 1H),1.46-1.35 (m, 4H), 1.31-1.26 (m, 1H); ES-LCMS m/z 405.0 [M+H]⁺.

I-206 & I-207

Step 1:(5R)-3-Bromo-5-[1-[(4-phenylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole&(5S)-3-Bromo-5-[1-[(4-phenylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 1-(bromomethyl)-4-phenyl-benzene (300 mg, 1.21 mmol, 1eq) in THE (6 mL) was added Et₃N (734.64 mg, 7.26 mmol, 1.01 mL, 6 eq)and 3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (419.56 mg, 1.09 mmol,8.99e-1 eq, TFA) under N2. The mixture was stirred at 25° C. for 4 h.TLC (PE/EtOAc=1/1, R_(f)=0.15) indicated starting material was consumedand many new spots formed. The mixture was concentrated and water (80mL) was added. The mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby flash silica gel chromatography (From PE/EtOAc=1/0 to 1/1,R_(f)=0.15) to yield the product which was separated by SFC (column:DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂OEtOH]; B %: 40%-40%, min) to yield(5R)-3-bromo-5-[1-[(4-phenylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole(43.17 mg, 108.11 umol, 8.9% yield, 100.0% purity, SFC: R_(t)=2.874 min,ee=99.56%, [α]^(22.4) _(D)=+90 (MeOH, c=0.050 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.26 (m, 2H), 1.49 (d,J=10.56 Hz, 2H), 1.67 (d, J=12.91 Hz, 1H), 1.88 (d, J=9.78 Hz, 2H), 2.84(d, J=9.78 Hz, 2H), 3.06 (dd, J=17.41, 8.80 Hz, 1H), 3.27 (d, J=10.96Hz, 1H), 3.46 (s, 2H), 4.40-4.48 (m, 1H), 7.30-7.39 (m, 3H), 7.44 (t,J=7.63 Hz, 2H), 7.61 (dd, J=16.82, 7.83 Hz, 4H); ES-LCMS m/z 399.1,401.1 [M+H]⁺ and(5S)-3-bromo-5-[1-[(4-phenylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole(46.53 mg, 116.52 umol, 9.6% yield, 100.0% purity, SFC: R_(t)=3.313 min,ee=99.50%, [α]^(22.1) _(D)=−96 (MeOH, c=0.050 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.25 (m, 2H), 1.48 (d,J=10.17 Hz, 2H), 1.67 (d, J=13.30 Hz, 1H), 1.83-1.94 (m, 2H) 2.84 (d,J=10.17 Hz, 2H), 3.06 (dd, J=17.41, 8.80 Hz, 1H), 3.27 (d, J=10.96 Hz,1H), 3.46 (s, 2H), 4.35-4.52 (m, 1H), 7.30-7.38 (m, 3H), 7.44 (t, J=7.63Hz, 2H), 7.61 (dd, J=17.41, 8.02 Hz, 4H); ES-LCMS m/z 399.1, 401.1[M+H]⁺.

I-208

Step 1: 04-Benzyl 07-ethyl(1R,6S,7S)-4-azabicyclo[4.1.0]heptane-4,7-dicarboxylate

To a mixture of benzyl 3,6-dihydro-2H-pyridine-1-carboxylate (2 g, 9.21mmol, 1 eq) and rhodium(II) acetate (40 mg, 181.00 μmol, 1.97e-2 eq) in1,2-dichloroethane (80 mL) was added a solution of ethyl 2-diazoacetate(5.25 g, 46.03 mmol, 4.82 mL, 5 eq) in 1,2-dichloroethane (20 mL)dropwise under N₂ atmosphere at 80° C. The mixture was stirred at underN₂ atmosphere at 80° C. for 5 h. The reaction mixture was concentratedunder reduced pressure to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 3/1, TLC:PE/EtOAc=3/1, R_(f)=0.41) to yield 04-benzyl 07-ethyl(1R,6S,7S)-4-azabicyclo[4.1.0]heptane-4,7-dicarboxylate (1.5 g, 4.61mmol, 50.1% yield, 93.2% purity) as colorless oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.42-7.30 (m, 5H), 5.13 (s, 2H), 4.15-4.09 (m, 2H), 4.00(d, J=13.7 Hz, 1H), 3.59 (d, J=13.3 Hz, 1H), 3.56-3.48 (m, 1H), 3.05(ddd, J=5.5, 8.9, 13.8 Hz, 1H), 2.04-1.96 (m, 1H), 1.88-1.78 (m, 1H),1.76-1.66 (m, 2H), 1.49 (t, J=4.3 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H);ES-LCMS m/z 304.3 [M+H]⁺.

Step 2:(1R,6S,7S)-4-Benzyloxycarbonyl-4-azabicyclo[4.1.0]heptane-7-carboxylicacid

To a solution of 04-benzyl 07-ethyl(1R,6S,7S)-4-azabicyclo[4.1.0]heptane-4,7-dicarboxylate (1 g, 3.07 mmol,1 eq) in THE (10 mL), MeOH (4 mL) and H₂O (4 mL) was added LiOH.H₂O (650mg, 15.49 mmol, 5.04 eq). The mixture was stirred at 25° C. for 12 h.TLC (PE/EtOAc=3/1, R_(f)=0.05) showed the starting material was consumedcompletely. The reaction mixture was diluted with H₂O (50 mL) andextracted with EtOAc (50 mL×2). The organic layer was discarded. Theaqueous layer was acidified with aqueous HCl (2 M) until pH=5 andextracted with EtOAc (50 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield(1R,6S,7S)-4-benzyloxycarbonyl-4-azabicyclo[4.1.0]heptane-7-carboxylicacid (800 mg, 2.91 mmol, 94.6% yield, 100.0% purity) as a colorless gum,which was used in the next step without further purification. ¹H NMR(500 MHz, CD₃OD) δ ppm 7.38-7.30 (m, 5H), 5.16-5.10 (m, 2H), 3.98 (d,J=14.0 Hz, 1H), 3.73 (d, J=7.9 Hz, 1H), 3.56-3.46 (m, 1H), 3.16-3.06 (m,1H), 2.10-2.03 (m, 1H), 1.96-1.79 (m, 1H), 1.76-1.69 (m, 2H), 1.60-1.37(m, 1H); ES-LCMS m/z 276.2 [M+H]⁺.

Step 3: Benzyl(1R,6R,7S)-7-(tert-butoxycarbonylamino)-4-azabicyclo[4.1.0]heptane-4-carboxylate

To a solution of(1R,6S,7S)-4-benzyloxycarbonyl-4-azabicyclo[4.1.0]heptane-7-carboxylicacid (750 mg, 2.72 mmol, 1 eq) and Et₃N (303.24 mg, 3.00 mmol, 417.11μL, 1.1 eq) in acetone (15 mL) was added ethyl chloroformate (355 mg,3.27 mmol, 311.40 μL, 1.2 eq) dropwise at 0° C. The mixture was stirredat 0° C. for 0.5 h. A solution of NaN₃ (1.01 g, 15.54 mmol, 5.70 eq) inH₂O (7.5 mL) was added slowly at 0° C. The mixture was stirred at 25° C.for 2 h. The mixture was diluted with water (20 mL) and extracted withEtOAc (20 mL×3). The aqueous layer was poured into NaClO (100 mL)slowly. The organic layer was dried over Na₂SO₄ and filtered and toluene(40 mL) was added. The mixture was concentrated under reduced pressureat 30° C. to remove acetone and EtOAc. The residue was added to amixture of 4-methylbenzenesulfonic acid; pyridine (5 mg, 19.90 μmol,7.30e-3 eq) in t-BuOH (10 mL) and toluene (30 mL) at 100° C. slowly. Themixture was stirred at 100° C. for 12 h. The reaction mixture wasdiluted with H₂O (50 mL) and extracted with EtOAc (50 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 4/1, TLC: PE/EtOAc=2/1,R_(f)=0.40) to yield benzyl(1R,6R,7S)-7-(tert-butoxycarbonylamino)-4-azabicyclo[4.1.0]heptane-4-carboxylate(780 mg, 2.22 mmol, 81.3% yield, 98.4% purity) as a colorless gum. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.40-7.30 (m, 5H), 5.12 (s, 2H), 4.76-4.66(m, 1H), 3.98-3.88 (m, 1H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 1H),3.10-3.00 (m, 1H), 2.39-2.14 (m, 1H), 1.99 (d, J=5.8 Hz, 1H), 1.88-1.78(m, 1H), 1.45 (s, 9H), 1.25-1.13 (m, 2H); ES-LCMS m z 369.2 [M+Na]⁺.

Step 4: tert-ButylN-[(1R,6R,7S)-4-azabicyclo[4.1.0]heptan-7-yl]carbamate

A mixture of benzyl(1R,6R,7S)-7-(tert-butoxycarbonylamino)-4-azabicyclo[4.1.0]heptane-4-carboxylate(730 mg, 2.07 mmol, 1 eq) and Pd(OH)₂ (0.2 g, 20% purity) in MeOH (30mL) was stirred under H₂ (15 psi) at 25° C. for 2 h. TLC (PE/EtOAc=2/1,R_(f)=0.05) showed the starting material was consumed completely. Themixture was filtered. The filtrate was concentrated under reducedpressure to yield tert-butylN-[(1R,6R,7S)-4-azabicyclo[4.1.0]heptan-7-yl]carbamate (400 mg, 1.88mmol, 91.1% yield, N/A purity) as a pale yellow gum, which was used inthe next step without further purification. ¹H NMR (500 MHz, CD₃OD) δppm 3.21-3.14 (m, 1H), 3.02 (d, J=13.4 Hz, 1H), 2.56-2.50 (m, 1H),2.48-2.43 (m, 1H), 2.36 (t, J=3.4 Hz, 1H), 1.98-1.92 (m, 1H), 1.80-1.70(m, 1H), 1.45 (s, 9H), 1.17-1.11 (m, 1H), 1.08-1.02 (m, 1H).

Step 5: tert-ButylN-[(1R,6R,7S)-4-[[4-(trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-yl]carbamate

A mixture of tert-butylN-[(1R,6R,7S)-4-azabicyclo[4.1.0]heptan-7-yl]carbamate (50 mg, 235.53μmol, 1 eq), 1-(bromomethyl)-4-(trifluoromethyl)benzene (50 mg, 209.18μmol, 8.88e-1 eq) and DIEA (100 mg, 773.74 μmol, 134.77 μL, 3.29 eq) inDCM (3 mL) was stirred at 25° C. for 12 h. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with DCM (20 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by preparative TLC(PE/EtOAc=2/1, R_(f)=0.30) to yield tert-butylN-[(1R,6R,7S)-4-[[4-(trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-yl]carbamate(50 mg, 132.15 μmol, 56.1% yield, 97.9% purity) as a colorless gum. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.55 (d, J=7.9 Hz, 2H), 7.40 (d, J=7.9 Hz,2H), 4.70 (br s, 1H), 3.54-3.33 (m, 2H), 2.89 (d, J=9.9 Hz, 1H),2.62-2.52 (m, 2H), 2.26-2.16 (m, 1H), 2.03-1.91 (m, 2H), 1.73-1.58 (m,1H), 1.45 (s, 9H), 1.22-1.04 (m, 2H); ES-LCMS m/z 371.7 [M+H]⁺.

Step 6:(1R,6R,7S)-4-[[4-(Trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-amine

To a solution of tert-butylN-[(1R,6R,7S)-4-[[4-(trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-yl]carbamate(50 mg, 132.15 μmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01mmol, 2 mL, 204.40 eq). The mixture was stirred at 20° C. for 0.5 h. TLC(PE/EtOAc=1/1, R_(f)=0.05) showed the starting material was consumedcompletely. The reaction mixture was concentrated under reduced pressureto yield(1R,6R,7S)-4-[[4-(trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-amine(65 mg, 130.43 μmol, 98.7% yield, N/A purity, 2TFA) as a colorless gum,which was used in the next step without further purification.

Step 7:N-[(1R,6R,7S)-4-[[4-(Trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-yl]prop-2-enamide

To a solution of(1R,6R,7S)-4-[[4-(trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-amine(65 mg, 130.43 μmol, 1 eq, 2TFA) and DIEA (84.29 mg, 652.17 μmol, 113.60μL, 5 eq) in DCM (10 mL) was added prop-2-enoyl chloride (12.21 mg,134.90 μmol, 11 μL, 1.03 eq). The mixture was stirred at 20° C. for 1 h.The reaction mixture was concentrated under reduced pressure to yield aresidue which was purified by preparative HPLC (column: PhenomenexSynergi C18 150*30 mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %:13%-33%, 9 min). The desired fraction was basified with saturatedaqueous NaHCO₃ until pH=8 and extracted with EtOAc (50 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was dissolved in MeCN (15 mL)and water (15 mL) and then lyophilized to yieldN-[(1R,6R,7S)-4-[[4-(trifluoromethyl)phenyl]methyl]-4-azabicyclo[4.1.0]heptan-7-yl]prop-2-enamide(21.99 mg, 67.80 μmol, 52.0% yield, 100.0% purity) as a white solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.56 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.5 Hz,2H), 6.28 (dd, J=1.1, 16.9 Hz, 1H), 6.03 (dd, J=10.4, 16.9 Hz, 1H), 5.68(br s, 1H), 5.62 (dd, J=1.1, 10.2 Hz, 1H), 3.48 (d, J=12.7 Hz, 2H), 2.96(d, J=11.3 Hz, 1H), 2.84 (q, J=3.2 Hz, 1H), 2.68-2.48 (m, 1H), 2.27 (d,J=6.3 Hz, 1H), 2.07-1.89 (m, 3H), 1.25 (d, J=12.4 Hz, 1H), 1.20-1.10 (m,1H); ES-LCMS m/z 325.3 [M+H]⁺.

I-211

Step 1: 1-[(3R)-3-Aminopyrrolidin-1-yl]prop-2-en-1-one

A solution of tert-butyl N-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate(500 mg, 1.87 mmol, 1 eq) in DCM (6 mL) and TFA (2 mL) was stirred at28° C. for 1 h. TLC (PE/EtOAc=1/1, R_(f)=0.01) indicated startingmaterial was consumed completely. The mixture was filtered andconcentrated under reduced pressure to yield1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (450 mg, 1.77 mmol, 94.5%yield, N/A purity, TFA) as a light yellow gum, which was used in thenext step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.05 (br s, 2H), 6.62-6.43 (m, 1H), 6.22-6.04 (m, 1H), 5.66 (dd, J=2.4,10.3 Hz, 1H), 3.83-3.75 (m, 1H), 3.75-3.65 (m, 1H), 3.65-3.56 (m, 1H),3.56-3.50 (m, 1H), 3.49-3.42 (m, 1H), 2.32-2.06 (m, 1H), 2.04-1.83 (m,1H).

Step 2:1-[(3R)-3-[[4-(Trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one

To a solution of 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (450 mg,1.77 mmol, 1 eq, TFA) and DIEA (1.14 g, 8.85 mmol, 1.54 mL, 5 eq) in DCM(10 mL) was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (338.51 mg,1.42 mmol, 218.39 μL, 0.8 eq). The mixture was stirred at 28° C. for 12h. The mixture was diluted with water (10 mL) and extracted with EtOAc(10 mL×3). The combined organic layers were dried over Na₂SO₄, filteredand concentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from EtOAc/MeOH=100/1 to20/1, TLC: EtOAc/MeOH=10/1, R_(f)=0.40) and preparative HPLC (column:Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 29%-59%, 10 min), followed by lyophilization toyield1-[(3R)-3-[[4-(trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one(18.47 mg, 60.36 μmol, 3.4% yield, 97.5% purity, [α]^(23.0) _(D)=+5.582(MeOH, c=0.025 g/100 mL)) as colorless oil. ¹H NMR (400 MHz, CD₃OD) δppm 7.65-7.61 (m, 2H), 7.58-7.54 (m, 2H), 6.57 (ddd, J=10.4, 16.9, 18.1Hz, 1H), 6.28-6.22 (m, 1H), 5.72 (ddd, J=2.0, 5.3, 10.4 Hz, 1H),3.89-3.86 (m, 2H), 3.81-3.75 (m, 1H), 3.74-3.52 (m, 2H), 3.49-3.42 (m,1H), 3.40-3.36 (m, 1H), 2.20-2.10 (m, 1H), 1.97-1.79 (m, 1H); ES-LCMSm/z 299.2 [M+H]⁺.

I-212

Step 1:N-[(1R,5S)-3-[[4-(Trifluoromethoxy)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(80.67 mg, 424.06 μmol, 1 eq, HCl) in DMF (30 mL) was added DIEA (328.84mg, 2.54 mmol, 443.18 μL, 6 eq) and1-(bromomethyl)-4-(trifluoromethoxy)benzene (108.15 mg, 424.06 μmol,68.02 μL, 1 eq). The mixture was stirred at 20° C. for 12 h. The mixturewas concentrated to yield a residue which was purified by preparativeHPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water (10mM NH₄HCO₃)-ACN]; B %: 35%-65%, 10 min), followed by lyophilization toyieldN-[(1R,5S)-3-[[4-(trifluoromethoxy)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(36.75 mg, 112.62 μmol, 26.6% yield, 100.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.29 (s, 2H), 7.14 (d, J=8.1 Hz, 2H), 6.28(dd, J=1.3, 17.0 Hz, 1H), 6.02 (dd, J=10.3, 17.1 Hz, 1H), 5.62 (dd,J=1.2, 10.3 Hz, 1H), 5.51 (br s, 1H), 3.57 (s, 2H), 3.15-3.09 (m, 3H),2.41 (d, J=8.6 Hz, 2H), 1.66-1.56 (m, 2H); ES-LCMS m/z 327.2 [M+H]⁺.

I-213 & I-214

Step 1:(5R)-3-Bromo-5-[1-[(4-tert-butylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[1-[(4-tert-butylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (400 mg,1.04 mmol, 1 eq, TFA) in THE (10 mL) was added DIEA (670.18 mg, 5.19mmol, 903.20 μL, 5 eq) and 1-(bromomethyl)-4-tert-butyl-benzene (353.34mg, 1.56 mmol, 284.96 μL, 1.5 eq). The mixture was stirred under N₂atmosphere at 20° C. for 4 h. The reaction mixture was diluted withwater (50 mL) then extracted with EtOAc (30 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=1/1,R_(f)=0.25) to yield the compound which was separated by SFC (column:DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1%NH₃H₂O/EtOH]; B %: 20%-20%) to yield peak 1 and peak 2. Peak 1 wasconcentrated under reduced pressure to yield a residue which waslyophilized to yield(5R)-3-bromo-5-[1-[(4-tert-butylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole(63 mg, 166.08 μmol, 16.0% yield, 100.0% purity, SFC: R_(t)=3.248,ee=100.0%, [α]^(21.7) _(D)=+69.8 (MeOH, c=0.43 g/100 mL)) as yellow oil.¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.32 (d, J=7.8 Hz, 2H), 7.19 (d, J=7.6Hz, 2H), 4.48-4.41 (m, 1H), 3.38 (s, 2H), 3.30 (s, 1H), 3.07 (dd, J=8.8,17.5 Hz, 1H), 2.80 (d, J=9.6 Hz, 2H), 1.90-1.78 (m, 2H), 1.67 (d, J=10.5Hz, 1H), 1.48 (d, J=8.4 Hz, 2H), 1.27 (s, 9H), 1.22-1.14 (m, 2H);ES-LCMS m/z 379.2, 381.2 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was lyophilized to yield(5S)-3-bromo-5-[1-[(4-tert-butylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole(68.12 mg, 172.72 μmol, 16.7% yield, 96.2% purity, SFC: R_(t)=3.533,ee=97.3%, [α]^(21.7) _(D)=−77.7 (MeOH, c=0.43 g/100 mL)) as yellow oil.¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.32 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.9Hz, 2H), 4.50-4.41 (m, 1H), 3.38 (s, 2H), 3.31-3.27 (m, 1H), 3.07 (dd,J=8.8, 17.6 Hz, 1H), 2.81 (d, J=9.0 Hz, 2H), 1.91-1.78 (m, 2H), 1.67 (d,J=12.5 Hz, 1H), 1.48 (d, J=10.4 Hz, 2H), 1.27 (s, 9H), 1.23-1.13 (m,2H); ES-LCMS m/z 379.2, 381.2 [M+H]⁺.

I-220

Step 1:N-[(1R,5S)-3-[(4-tert-Butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a stirred solution ofN-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (100 mg, 424.06μmol, 1 eq, HCl) in DMF (3 mL) was added DIEA (219.23 mg, 1.70 mmol,295.45 μL, 4 eq) and 1-(bromomethyl)-4-tert-butyl-benzene (115.58 mg,508.87 μmol, 93.21 μL, 1.2 eq). The reaction mixture was stirred at 28°C. for 4 h. The reaction was concentrated under reduced pressure toyield a residue which was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 um; mobile phase: [water (0.05% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 42%-72%, 10 min). The desired fraction waslyophilized to yieldN-[(1R,5S)-3-[(4-tert-butylphenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(20.77 mg, 66.71 μmol, 15.7% yield, 95.9% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.31 (d, J=8.31 Hz, 2H), 7.19 (d, J=8.07 Hz,2H), 6.27 (dd, J=17.00, 1.34 Hz, 1H), 6.06-5.97 (m, 1H), 5.61 (dd,J=10.27, 1.47 Hz, 1H), 5.50 (s, 1H), 3.55 (s, 2H), 3.18-3.07 (m, 3H),2.41 (d, J=8.56 Hz, 2H), 1.54 (s, 2H), 1.32 (s, 9H); ES-LCMS m/z 299.3[M+H]⁺.

I-222

Step 1:N-[(1R,5S)-3-[[3-(Trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(100 mg, 525.65 μmol, 1 eq, HCl) in DMF (5 mL) was added1-(bromomethyl)-3-(trifluoromethyl)benzene (140 mg, 585.70 μmol, 89.17μL, 1.11 eq) and DIEA (203.81 mg, 1.58 mmol, 274.68 μL, 3 eq). Themixture was stirred at 25° C. for 16 h. The reaction mixture wasconcentrated to yield a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.05%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 35%-65%, 10 min), followed bylyophilization to yieldN-[(1R,5S)-3-[[3-(trifluoromethyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(16.7 mg, 53.82 μmol, 10.2% yield, 100.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.51-7.46 (m, 3H), 7.44-7.39 (m, 1H), 6.28(dd, J=1.3, 17.0 Hz, 1H), 6.02 (dd, J=10.3, 16.9 Hz, 1H), 5.63 (dd,J=1.2, 10.3 Hz, 1H), 5.50 (s, 1H), 3.62 (s, 2H), 3.13 (d, J=8.8 Hz, 3H),2.43 (d, J=8.8 Hz, 2H), 1.57 (s, 1H), 1.60-1.57 (m, 1H); ES-LCMS m/z311.3 [M+H]⁺.

I-225 & I-226

Step 1:(5R)-3-Bromo-5-[1-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[1-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (300 mg,777.81 μmol, 1 eq, TFA) in DCM (10 mL) was added DIEA (804.19 mg, 6.22mmol, 1.08 mL, 8 eq) and1-(bromomethyl)-4-(trifluoromethylsulfanyl)benzene (253.03 mg, 933.37μmol, 117.02 μL, 1.2 eq). The mixture was stirred at 20° C. for 2 h. Thereaction mixture was quenched by addition of water (50 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers were washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water (0.04%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 59%-89%, 10 min) to yield the compoundwhich was separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm,5 um); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 20%-20%) to yield peak 1and peak 2. Peak 1 was concentrated under reduced pressure to yield(5R)-3-bromo-5-[1-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(70 mg, 165.37 μmol, 21.3% yield, 100.0% purity, SFC: R_(t)=3.153,ee=98.1%; [α]^(24.0) _(D)=+71.8 (MeOH, c=0.078 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.66 (d, J=7.8 Hz, 2H), 7.45 (d,J=8.2 Hz, 2H), 4.51-4.39 (m, 1H), 3.50 (s, 2H), 3.32-3.25 (m, 1H), 3.07(dd, J=8.6, 17.6 Hz, 1H), 2.80 (d, J=10.2 Hz, 2H), 1.99-1.85 (m, 2H),1.68 (d, J=12.9 Hz, 1H), 1.49 (d, J=12.1 Hz, 2H), 1.28-1.16 (m, 2H);ES-LCMS m/z 422.9, 424.9 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield(5S)-3-bromo-5-[1-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(55 mg, 129.93 μmol, 16.7% yield, 100.0% purity, SFC: R_(t)=3.307,ee=98.4%; [α]^(24.0) _(D)=−84.21 (MeOH, c=0.114 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.66 (d, J=7.8 Hz, 2H), 7.46 (d,J=8.2 Hz, 2H), 4.52-4.39 (m, 1H), 3.50 (s, 2H), 3.32-3.25 (m, 1H), 3.07(dd, J=8.6, 17.4 Hz, 1H), 2.80 (d, J=11.3 Hz, 2H), 1.97-1.84 (m, 2H),1.68 (d, J=12.5 Hz, 1H), 1.49 (d, J=12.1 Hz, 2H), 1.30-1.11 (m, 2H);ES-LCMS m z 422.8, 424.8 [M+H]⁺.

I-231

Step 1:N-[(1R,5S)-3-[(4-Chlorophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(50 mg, 262.82 μmol, 1 eq, HCl) in DMF (5 mL) was added1-chloro-4-(chloromethyl)benzene (51.2 mg, 317.96 μmol, 1.21 eq) andDIEA (101.90 mg, 788.47 μmol, 137.34 μL, 3 eq). The mixture was stirredat 25° C. for 16 h. The reaction mixture was concentrated to yield aresidue which was purified by preparative HPLC (column: Agela DuraShellC18 150*25 mm*5 μm; mobile phase: [water (0.05% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 32%-62%, 10 min), followed by lyophilization toyieldN-[(1R,5S)-3-[(4-chlorophenyl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(12.99 mg, 46.70 μmol, 17.8% yield, 99.5% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.25 (s, 1H), 7.21-7.17 (m, 2H), 6.28 (dd,J=1.2, 16.9 Hz, 1H), 6.02 (dd, J=10.4, 17.0 Hz, 1H), 5.62 (dd, J=1.2,10.3 Hz, 1H), 5.50 (s, 1H), 3.54 (s, 2H), 3.11 (d, J=8.8 Hz, 3H), 2.40(d, J=8.8 Hz, 2H), 1.59 (s, 2H), 1.55 (s, 1H); ES-LCMS m/z 277.2 [M+H]⁺.

IK-232 & IK-233

Step 1: tert-ButylN-[1-[1-[4-(trifluoromethyl)phenyl]propyl]-4-piperidyl]carbamate

A mixture of 1-[4-(trifluoromethyl)phenyl]propan-1-one (300 mg, 1.48mmol, 1 eq) and tert-butyl N-(4-piperidyl)carbamate (297.19 mg, 1.48mmol, 1 eq) in Ti(i-PrO)₄ (1.27 g, 4.45 mmol, 1.31 mL, 3 eq) was stirredat 70° C. for 2 h. The mixture was cooled to 20° C. MeOH (10 mL) andNaBH₃CN (373.00 mg, 5.94 mmol, 4 eq) were added and the mixture wasstirred at 40° C. for 16 h. The reaction mixture was quenched by aqueousNaOH (10 mL, 1 M), filtered by celite and washed with MeOH (15 mL×2).MeOH was evaporated under vacuo. The residue was diluted with H₂O (20mL) and extracted with EtOAc (20 mL×2). The combined organic phases werewashed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water (0.04%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 60%-90%, 10 min) to yield tert-butylN-[1-[1-[4-(trifluoromethyl)phenyl]propyl]-4-piperidyl]carbamate (231mg, 537.97 μmol, 36.3% yield, 90.0% purity) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.65 (d, J=2.6 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz, 2H), 4.42-4.32 (m, 1H), 3.38-3.36 (m, 1H), 3.23 (dd,J=4.4, 8.5 Hz, 1H), 2.94-2.91 (m, 1H), 2.67 (d, J=11.3 Hz, 1H),2.13-2.02 (m, 1H), 1.98-1.79 (m, 5H), 1.76-1.68 (m, 1H), 1.42 (s, 9H),0.73-0.68 (m, 3H); ES-LCMS m/z 387.3 [M+H]⁺.

Step 2: 1-[1-[4-(Trifluoromethyl)phenyl]propyl]piperidin-4-amine

To a solution of tert-butylN-[1-[1-[4-(trifluoromethyl)phenyl]propyl]-4-piperidyl]carbamate (231mg, 537.97 μmol, 1 eq) in DCM (2.5 mL) was added TFA (0.5 mL) and themixture was stirred at 20° C. for 2 h. The mixture was concentrated toyield 1-[1-[4-(trifluoromethyl)phenyl]propyl]piperidin-4-amine (225 mg,393.68 μmol, 73.2% yield, 90.0% purity, 2TFA) as colorless gum, whichwas used in the next step without further purification. ¹H NMR (400 MHz,CD₃OD) δ ppm 7.82 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.36 (dd,J=4.2, 11.5 Hz, 1H), 3.57-3.42 (m, 2H), 3.16-3.06 (m, 1H), 2.96 (d,J=9.8 Hz, 2H), 2.30-2.17 (m, 4H), 2.07-1.89 (m, 2H), 0.75 (t, J=7.3 Hz,3H); ES-LCMS m/z 287.3 [M+H]⁺.

Step 3:N-[1-[(1R)-1-[4-(Trifluoromethyl)phenyl]propyl]-4-piperidyl]prop-2-enamideandN-[1-[(1S)-1-[4-(trifluoromethyl)phenyl]propyl]-4-piperidyl]prop-2-enamide

To a solution of1-[1-[4-(trifluoromethyl)phenyl]propyl]piperidin-4-amine (225 mg, 393.68μmol, 1 eq, 2TFA) and DIPEA (203.52 mg, 1.57 mmol, 274.28 μL, 4 eq) inDCM (10 mL) was added prop-2-enoyl chloride (35.63 mg, 393.68 μmol,32.10 μL, 1 eq) at 0° C. The mixture was stirred at 0° C. for 1 h. Themixture was concentrated to yield a residue which was purified bypreparative HPLC (column: Agela DuraShell C18 150*25 mm*5 um; mobilephase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 40%-70%, 10 min),followed by lyophilization to yield a product which was separated bychiral SFC (column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); mobilephase: [0.1% NH₃H₂O EtOH]; B %: 10%-10%) to yield peak 1 and peak 2.Peak 1 was concentrated under reduced pressure to yieldN-[1-[(1R)-1-[4-(trifluoromethyl)phenyl]propyl]-4-piperidyl]prop-2-enamide(12.89 mg, 37.29 μmol, 9.5% yield, 98.5% purity, SFC: R_(t)=2.537,ee=96.8%, [α]^(25.8) _(D)=+12.0 (MeOH, c=0.05 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.62 (d, J=7.3 Hz, 2H), 7.44 (d,J=7.3 Hz, 2H), 6.24 (dd, J=1.3, 17.0 Hz, 1H), 6.08-5.98 (m, 1H), 5.62(dd, J=1.1, 10.4 Hz, 1H), 5.56 (br s, 1H), 3.87-3.85 (m, 1H), 3.47-3.45(m, 1H), 3.23-3.20 (m, 1H), 2.92-2.90 (m, 1H), 2.28-2.25 (m, 1H),2.16-1.90 (m, 4H), 1.87-1.72 (m, 1H), 1.87-1.67 (m, 1H), 1.66-1.62 (m,1H), 1.47-1.44 (m, 1H), 0.72 (t, J=7.3 Hz, 3H); ES-LCMS m/z 341.1[M+H]⁺. Peak 2 was concentrated under reduced pressure to yieldN-[1-[(1S)-1-[4-(trifluoromethyl)phenyl]propyl]-4-piperidyl]prop-2-enamide(15.90 mg, 46.26 μmol, 11.8% yield, 99.0% purity, SFC: R_(t)=2.657,ee=96.3%, [α]^(25.8) _(D)=−6.52 (MeOH, c=0.046 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59 (d, J=7.8 Hz, 2H), 7.39 (d,J=7.6 Hz, 2H), 6.24 (dd, J=1.2, 16.9 Hz, 1H), 6.11-5.92 (m, 1H), 5.61(dd, J=1.2, 10.3 Hz, 1H), 5.49 (br s, 1H), 3.90-3.75 (m, 1H), 3.39-3.34(m, 1H), 3.12-3.09 (m, 1H), 2.83-2.79 (m, 1H), 2.21-2.18 (m, 1H),2.13-1.89 (m, 4H), 1.85-1.82 (m, 1H), 1.69-1.63 (m, 1H), 1.59-1.41 (m,1H), 0.71 (t, J=7.3 Hz, 3H); ES-LCMS m/z 341.1 [M+H]⁺.

I-234

Step 1:N-[(1R,5S)-3-[[4-(Trifluoromethylsulfanyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(100 mg, 530.07 μmol, 1.2 eq, HCl) in DCM (5 mL) was added DIEA (171.27mg, 1.33 mmol, 230.82 μL, 3 eq) and1-(bromomethyl)-4-(trifluoromethylsulfanyl)benzene (119.75 mg, 441.73μmol, 1 eq). The mixture was stirred at 25° C. for 16 h. The reactionmixture were concentrated under reduced pressure to yield a residuewhich was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 μm; mobile phase: [water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN];B %: 44%-74%, 10 min), followed by lyophilization to yieldN-[(1R,5S)-3-[[4-(trifluoromethylsulfanyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(40 mg, 116.83 μmol, 26.4% yield, 100.0% purity) as a white solid. ¹HNMR (500 MHz, CD₃OD) δ ppm 1.58 (s, 2H) 2.45 (d, J=8.39 Hz, 2H)3.05-3.12 (m, 3H) 3.64 (s, 2H) 5.62 (dd, J=9.61, 2.29 Hz, 1H) 6.11-6.24(m, 2H) 7.43 (d, J=8.09 Hz, 2H) 7.62 (d, J=8.09 Hz, 2H); ES-LCMS m z343.1 [M+H]⁺.

I-238 & I-239

Step 1: 2-Bromo-4-iodo-N-[3-(trifluoromethyl)phenyl]aniline

To a stirred solution of 2-bromo-4-iodo-aniline (2 g, 6.71 mmol, 1 eq)and [3-(trifluoromethyl)phenyl]boronic acid (1.28 g, 6.71 mmol, 1 eq) inDCM (40 mL) was added DIEA (2.60 g, 20.13 mmol, 3.51 mL, 3 eq) andCu(OAc)₂ (2.44 g, 13.42 mmol, 2 eq). The reaction mixture was stirred at25° C. for 24 h under O₂ (15 Psi). The reaction mixture was diluted withH₂O (30 mL) and extracted with DCM (50 mL×3). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to10/1, TLC: PE/EtOAc=10/1, R_(f)=0.47) to yield2-bromo-4-iodo-N-[3-(trifluoromethyl)phenyl]aniline (1.4 g, 3.07 mmol,45.8% yield, 97.0% purity) as a red solid. ¹H NMR (500 MHz, CDCl₃) δ ppm7.86 (d, J=2.0 Hz, 1H), 7.49 (dd, J=1.9, 8.6 Hz, 1H), 7.46-7.40 (m, 1H),7.36 (s, 1H), 7.29 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.7 Hz, 1H), 6.15 (s,1H); ES-LCMS m/z 441.9, 443.9 [M+H]⁺.

Step 2: 2-Bromo-N-[3-(trifluoromethyl)phenyl]-4-vinyl-aniline

To a stirred solution of2-bromo-4-iodo-N-[3-(trifluoromethyl)phenyl]aniline (1.35 g, 2.96 mmol,1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (456.28 mg,2.96 mmol, 502.51 μL, 1 eq) in 1,4-dioxane (45 mL) and H₂O (15 mL) wasadded Cs₂CO₃ (1.93 g, 5.93 mmol, 2 eq) and Pd(dppf)Cl₂ (216.78 mg,296.26 μmol, 0.1 eq). The reaction mixture was bubbled with N₂ for 3times and stirred under N₂ atmosphere at 100° C. for 3 h. The reactionmixture was diluted with H₂O (30 mL) and extracted with EtOAc (60 mL×3).The combined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=1/1, R_(f)=0.45) to yield

2-bromo-N-[3-(trifluoromethyl)phenyl]-4-vinyl-aniline (600 mg, 1.58mmol, 53.3% yield, 90.0% purity) as colorless oil. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.64 (d, J=1.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.37 (s, 1H),7.31-7.29 (m, 1H), 7.29-7.28 (m, 1H), 7.26-7.21 (m, 2H), 6.61 (dd,J=10.8, 17.5 Hz, 1H), 6.24-6.12 (m, 1H), 5.65 (d, J=17.5 Hz, 1H), 5.20(d, J=10.8 Hz, 1H); ES-LCMS m/z 342.1, 344.1 [M+H]⁺.

Step 3:2-(1-Methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]-4-vinyl-aniline

To a stirred solution of2-bromo-N-[3-(trifluoromethyl)phenyl]-4-vinyl-aniline (300 mg, 789.12μmol, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (452.91 mg,1.18 mmol, 1.5 eq) in DMF (8 mL) was added Pd(PPh₃)₄ (91.19 mg, 78.91μmol, 0.1 eq). The reaction mixture was bubbled with N₂ for 3 times andstirred under N₂ atmosphere at 130° C. for 12 h. The reaction mixturewas diluted with H₂O (20 mL) and extracted with EtOAc (40 mL×3). Thecombined organic layers were washed with brine (40 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 2/1, TLC: PE/EtOAc=1/1, R_(f)=0.29) to yield2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]-4-vinyl-aniline(230 mg, 576.10 μmol, 73.0% yield, 86.0% purity) as red oil. ¹H NMR (500MHz, CDCl₃) δ ppm 10.09 (s, 1H), 7.53-7.50 (m, 2H), 7.44 (s, 1H),7.40-7.37 (m, 1H), 7.37-7.32 (m, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.22 (d,J=1.1 Hz, 1H), 7.12 (d, J=7.0 Hz, 1H), 6.72-6.66 (m, 1H), 5.65 (d,J=17.5 Hz, 1H), 5.14 (d, J=10.8 Hz, 1H), 3.77 (s, 3H); ES-LCMS m/z 344.3[M+H]⁺.

Step 4:4-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]anilineand4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline

To a stirred solution of2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]-4-vinyl-aniline(190 mg, 475.91 μmol, 1 eq) in EtOAc (15 mL) was added NaHCO₃ (399.81mg, 4.76 mmol, 10 eq) and dibromomethanone oxime (144.79 mg, 713.86μmol, 1.5 eq). The reaction mixture was stirred under N₂ atmosphere at25° C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.38) showed the startingmaterial was consumed completely and one new spot was detected. Thereaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 3/1, TLC: PE/EtOAc=1/1, R_(f)=0.38) to yieldcrude product which was separated by chiral SFC (column: DAICELCHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O IPA]; B%: 35%-35%) to yield peak 1 and peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (20 mL)and H₂O (40 mL) and lyophilized to yield4-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline(24.72 mg, 53.13 μmol, 11.2% yield, 100.0% purity, SFC: R_(t)=2.131,ee=100%, [α]^(24.8) _(D)=−187.755 (MeOH, c=0.049 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl3) δ ppm 10.16 (s, 1H), 7.52 (s, 1H), 7.47(d, J=2.1 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.39-7.33 (m,2H), 7.24 (d, J=1.2 Hz, 1H), 7.15 (d, J=6.6 Hz, 1H), 7.12 (dd, J=2.1,8.4 Hz, 1H), 5.68-5.62 (m, 1H), 3.81-3.74 (m, 3H), 3.59 (dd, J=10.8,17.4 Hz, 1H), 3.27 (dd, J=9.5, 17.3 Hz, 1H); ES-LCMS m/z 465.1, 467.1[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (20 mL) and H₂O (40 mL) andlyophilized to yield4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline(20.47 mg, 44.00 μmol, 9.2% yield, 100.0% purity, SFC: R_(t)=2.455,ee=98.52%, [α]24.7_(D)=+152.381 (MeOH, c=0.063 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 10.16 (s, 1H), 7.52 (s, 1H), 7.47(d, J=2.1 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.39-7.33 (m,2H), 7.24 (d, J=1.2 Hz, 1H), 7.15 (d, J=6.4 Hz, 1H), 7.12 (dd, J=2.2,8.5 Hz, 1H), 5.67-5.62 (m, 1H), 3.78 (s, 3H), 3.59 (dd, J=10.8, 17.4 Hz,1H), 3.28 (dd, J=9.5, 17.2 Hz, 1H); ES-LCMS m/z 465.1, 467.1 [M+H]⁺.

I-240 & I-241

Step 1: N-[(1R,5S)-3-Azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

tert-Butyl(1R,5S)-6-(prop-2-enoylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate(2.7 g, 10.59 mmol, 1 eq) was added to HCl/MeOH (20 mL, 4 M) and themixture was stirred at 20° C. for 30 min. The solvent was removed toyield N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (2.45 g,10.39 mmol, 98.1% yield, 80.0% purity, HCl) as brown gum, which was usedin the next step without purification. ¹H NMR (400 MHz, CD₃OD) δ ppm6.27-6.12 (m, 2H), 5.66 (dd, J=2.3, 9.4 Hz, 1H), 3.53-3.49 (m, 4H),2.73-2.70 (m, 1H), 2.02-1.98 (m, 2H).

Step 2:N-[(1R,5S)-3-[(1S)-1-[4-(Trifluoromethyl)phenyl]ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamideandN-[(1R,5S)-3-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(300 mg, 1.27 mmol, 1 eq, HCl) in MeOH (10 mL) was added Et₃N (257.46mg, 2.54 mmol, 354.14 μL, 2 eq) and stirred at 20° C. for 10 min.1-[4-(Trifluoromethyl)phenyl]ethanone (287.22 mg, 1.53 mmol, 1.2 eq) andTi(i-PrO)₄ (1.93 g, 6.78 mmol, 2 mL, 5.33 eq) were added and the mixturewas stirred at 70° C. for 2 h. The mixture was cooled to 40° C. andNaBH₃CN (399.73 mg, 6.36 mmol, 5 eq) was added. The mixture was stirredat 40° C. for 16 h. TLC (MeOH/DCM=1/10, R_(f)=0.61) indicated thestarting material was consumed completely and one new spot formed. Thereaction mixture was quenched by aqueous NaOH (15 mL, 1M), filtered bycelite and washed with MeOH (15 mL×2). The mixture was concentrated toyield a residue which was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.05% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 40%-70%, 10 min), followed by lyophilization toyield a product which was separated by SFC (column: DAICEL CHIRALPAKAD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O IPA]; B %:15%-15%) to yield peak 1 and peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (10 mL)and H₂O (20 mL) and lyophilized to yieldN-[(1R,5S)-3-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(23.69 mg, 72.24 μmol, 5.7% yield, 98.9% purity, SFC: R_(t)=3.222,ee=97.88%, [α]^(23.5) _(D)=−45.16 (MeOH, c=0.031 g/100 mL)) as a whitesolid. 1H NMR (500 MHz, CDCl₃) δ ppm 7.53 (d, J=7.9 Hz, 2H), 7.37 (d,J=7.9 Hz, 2H), 6.27 (dd, J=1.4, 16.9 Hz, 1H), 6.01 (dd, J=10.2, 16.9 Hz,1H), 5.61 (dd, J=1.3, 10.3 Hz, 1H), 5.50 (br s, 1H), 3.43-3.21 (m, 2H),3.20-3.10 (m, 1H), 2.80 (d, J=9.2 Hz, 1H), 2.48 (d, J=5.3 Hz, 1H), 2.18(d, J=6.0 Hz, 1H), 1.67-1.60 (m, 1H), 1.52-1.48 (m, 1H), 1.31-1.28 (m,3H); ES-LCMS m/z 325.2 [M+H]⁺. Peak 2 was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (10 mL) and H₂O(20 mL) and lyophilized to yieldN-[(1R,5S)-3-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(30.04 mg, 92.62 μmol, 7.3% yield, 100.0% purity, SFC: R_(t)=3.308,ee=96.6%, [α]^(23.5) _(D)=+25.00 (MeOH, c=0.032 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.55 (d, J=6.1 Hz, 2H), 7.48-7.32(m, 2H), 6.26 (d, J=16.6 Hz, 1H), 6.03 (dd, J=10.5, 16.7 Hz, 1H), 5.61(d, J=10.4 Hz, 1H), 3.34-3.30 (m, 2H), 3.17-3.15 (m, 1H), 2.86-2.82 (m,1H), 2.53-2.51 (m, 1H), 2.23-2.19 (m, 1H), 1.65-1.62 (m, 1H), 1.55-1.45(m, 1H), 1.32-1.32 (m, 3H); ES-LCMS m/z 325.2 [M+H]⁺.

I-249

Step 1: 3-Bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (600mg, 1.69 mmol, 1 eq) in DCM (9 mL) was added TFA (3 mL). The mixture wasstirred at 25° C. for 2 h. TLC (PE/EtOAc=3/1, R_(f)=0) indicatedstarting material was consumed completely and one new spot formed. Thereaction mixture was concentrated under reduced pressure to yield3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (300 mg, 810.56μmol, 95.8% yield, 90.0% purity, TFA) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.74-4.63 (m, 1H), 3.49-3.40 (m, 1H), 3.33-3.20 (m, 2H),3.16-3.05 (m, 2H), 2.92-2.80 (m, 1H), 2.62-2.50 (m, 1H), 2.07-1.98 (m,1H), 1.66-1.54 (m, 1H), 1.32 (d, J=1.6 Hz, 1H).

Step 2:(5S)-3-Bromo-5-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a solution of 3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole(200 mg, 821.62 μmol, 1 eq) in DMF (4 mL) was added DIEA (849.49 mg,6.57 mmol, 1.14 mL, 8 eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene(196.39 mg, 821.62 μmol, 125.09 μL, 1 eq). The mixture was stirred at20° C. for 12 h. The reaction mixture was quenched by addition of water(50 mL) and extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine (40 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (Agela DuraShell C18 150*25 mm*5 um; mobilephase: [column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water(0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 48%-78%, 10 min) to yield theproduct which was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂O/EtOH]; B %: 15%-15%) toyield(5S)-3-bromo-5-[(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(27.18 mg, 72.06 μmol, 8.8% yield, 100.0% purity, SFC: R_(t)=1.972,ee=97.5%; [α]^(24.0) _(D)=+69.3 (MeOH, c=0.179 g/100 mL)) as yellow oil.¹H NMR (500 MHz, CDCl₃) δ ppm 7.58 (s, 1H), 7.55-7.48 (m, 2H), 7.47-7.41(m, 1H), 4.67 (td, J=8.4, 10.4 Hz, 1H), 3.71-3.62 (m, 2H), 3.26 (dd,J=10.4, 17.2 Hz, 1H), 2.95 (dd, J=8.4, 17.2 Hz, 1H), 2.73-2.62 (m, 2H),2.61-2.46 (m, 3H), 2.04-1.95 (m, 1H), 1.49 (qd, J=6.7, 13.6 Hz, 1H);ES-LCMS m/z 376.8, 378.8 [M+H]⁺.

I-253 & I-254

Step 1: tert-Butyl6-prop-2-enoyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-1-carboxylate

To a solution of tert-butyl2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b]pyridine-1-carboxylate (300.00mg, 1.33 mmol, 1 eq), TEA (402.41 mg, 3.98 mmol, 553.52 μL, 3 eq) in DCM(20 mL) was added prop-2-enoyl chloride (149.97 mg, 1.66 mmol, 135.11μL, 1.25 eq) at 0° C. under N₂ atmosphere. The mixture was stirred at20° C. for 1 h. TLC (PE/EtOAc=1/1, R_(f)=0.45) indicated the startingmaterial was consumed completely and one new spot formed. The reactionmixture was concentrated to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=1/0 to 1/1, TLC: PE/EtOAc=1/1,R_(f)=0.45) to yield tert-butyl6-prop-2-enoyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-1-carboxylate(320 mg, 1.11 mmol, 83.5% yield, 97.0% purity) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 6.51-6.32 (m, 2H), 5.70 (dd, J=5.1, 7.4 Hz, 1H),4.74 (br s, 1H), 4.20-3.92 (m, 1H), 3.85-3.28 (m, 4H), 2.88-2.60 (m,1H), 2.32-2.16 (m, 1H), 1.87-1.64 (m, 2H), 1.47 (d, J=4.3 Hz, 9H),1.45-1.19 (m, 2H); ES-LCMS m/z 281.1 [M+H].

Step 2:1-(1,2,3,4,4a,5,7,7a-Octahydropyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one

To a solution of tert-butyl6-prop-2-enoyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-1-carboxylate(310.00 mg, 1.07 mmol, 1 eq) in DCM (18 mL) was added HCl/MeOH (4 M, 6mL, 22.38 eq). The mixture was stirred at 15° C. for 2 h. TLC(PE/EtOAc=3/1, R_(f)=0.00) indicated the starting material was consumedcompletely and one new spot formed. The reaction mixture wasconcentrated to yield1-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one(230 mg, 1.06 mmol, 98.9% yield, N/A purity, HCl) as a white solid,which was used in the next step without further purification. ¹H NMR(500 MHz, CD₃OD) δ ppm 6.67-6.52 (m, 1H), 6.37-6.27 (m, 1H), 5.81 (dd,J=1.7, 10.4 Hz, 1H), 3.96-3.75 (m, 4H), 3.65-3.42 (m, 1H), 3.36-3.32 (m,1H), 3.14-2.98 (m, 1H), 2.91-2.79 (m, 1H), 2.00-1.72 (m, 4H).

Step 3:1-[(4aS,7aS)-1-[[4-(Trifluoromethyl)phenyl]methyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridin-6-yl]prop-2-en-1-oneand1-[(4aR,7aR)-1-[[4-(trifluoromethyl)phenyl]methyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridin-6-yl]prop-2-en-1-one

To a solution of1-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)prop-2-en-1-one(80 mg, 369.16 μmol, 1 eq, HCl) in MeCN (5 mL) was added K₂CO₃ (153.07mg, 1.11 mmol, 3 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene(97.07 mg, 406.08 μmol, 62.62 μL, 1.1 eq) under N₂ atmosphere. Themixture was stirred at 20° C. for 2 h. The reaction mixture was filteredand the filtrate was concentrated to yield a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=1/0 to 1/1, TLC:PE/EtOAc=1/1, R_(f)=0.46) to yield a product (100 mg). The product wasfurther separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250mm*30 mm, 5 μm); mobile phase: [0.1% NH₃.H₂O/EtOH]; B %: 20%-20%) toyield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressureto yield a residue which was purified by preparative HPLC (column: WelchXtimate C18 150*25 mm*5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 40%-70%, 10 min), followed by lyophilization to yield1-[(4aS,7aS)-1-[[4-(trifluoromethyl)phenyl]methyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridin-6-yl]prop-2-en-1-one(17.26 mg, 51.01 μmol, 13.8% yield, 100.0% purity, R_(t)=2.891, ee=100%,[α]^(18.2) _(D)=−4.666 (MeOH, c=0.061 g/100 mL)) as a white solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.59-7.52 (m, 2H), 7.41 (t, J=7.3 Hz, 2H),6.51-6.28 (m, 2H), 5.74-5.59 (m, 1H), 3.95-3.84 (m, 1H), 3.81-3.64 (m,1H), 3.64-3.47 (m, 3H), 3.47-3.33 (m, 1H), 3.22-3.03 (m, 1H), 2.69-2.57(m, 1H), 2.47-2.19 (m, 2H), 1.77-1.64 (m, 2H), 1.59-1.48 (m, 2H);ES-LCMS m/z 339.3 [M+H]⁺. Peak 2 was concentrated under reduced pressureto yield a residue which was purified by preparative HPLC (column: WelchXtimate C18 150*25 mm*5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 39%-69%, 10 min), followed by lyophilization to yield1-[(4aR,7aR)-1-[[4-(trifluoromethyl)phenyl]methyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridin-6-yl]prop-2-en-1-one(17.26 mg, 51.01 μmol, 13.8% yield, 100.0% purity, R_(t)=3.253,ee=97.58%, [α]^(18.2) _(D)=+9.152 (MeOH, c=0.055 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.59-7.51 (m, 2H), 7.41 (t, J=7.3Hz, 2H), 6.52-6.29 (m, 2H), 5.75-5.57 (m, 1H), 3.95-3.84 (m, 1H),3.81-3.70 (m, 1H), 3.67-3.46 (m, 3H), 3.46-3.33 (m, 1H), 3.22-3.03 (m,1H), 2.68-2.58 (m, 1H), 2.49-2.19 (m, 2H), 1.75-1.65 (m, 2H), 1.57-1.45(m, 2H); ES-LCMS m/z 339.3 [M+H]⁺.

I-256

Step 1:N-[(1R,5S)-3-[[4-(Trifluoromethylsulfonyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide

To a solution of 1-(bromomethyl)-4-(trifluoromethylsulfonyl)benzene (50mg, 164.96 μmol, 1 eq) in DCM (5 mL) was added DIEA (63.96 mg, 494.89μmol, 86.20 μL, 3 eq) andN-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (46.68 mg,197.96 μmol, 1.2 eq, HCl). The mixture was stirred at 25° C. for 12 h.The reaction mixture were concentrated under reduced pressure to yield aresidue which was purified by preparative HPLC (column: Agela DuraShell(C18 150*25 mm*5 μm; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 36%-66%, 10 min), followed by lyophilization toyieldN-[(1R,5S)-3-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide(25 mg, 66.78 μmol, 40.4% yield, 100.0% purity) as a white solid. ¹H NMR(500 MHz, CD₃OD) δ ppm 8.02 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H),6.25-6.12 (m, 2H), 5.63 (dd, J=2.4, 9.7 Hz, 1H), 3.77 (s, 2H), 3.13 (d,J=8.9 Hz, 3H), 2.48 (d, J=8.7 Hz, 2H), 1.60 (d, J=1.1 Hz, 2H); ES-LCMSm/z 375.1 [M+H]⁺.

I-257 & I-258

Step 1: 5-Bromo-2-iodo-aniline

A mixture of 4-bromo-1-iodo-2-nitro-benzene (2 g, 6.10 mmol, 1 eq),NH₄Cl (1.63 g, 30.50 mmol, 5 eq), Fe (1.70 g, 30.50 mmol, 5 eq) in EtOH(8 mL), THE (8 mL) and H₂O (8 mL) was degassed and purged with N₂ for 3times. The mixture was stirred under N₂ atmosphere at 70° C. for 3 h.TLC (PE/EtOAc=5/1, R_(f)=0.45) indicated starting material was consumedcompletely and two new spots formed. The mixture was concentrated andwater (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3)and the combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to yield a residue which waspurified by flash silica gel chromatography (From PE/EtOAc=1/0 to 5/1,R_(f)=0.45) to yield 5-bromo-2-iodo-aniline (1.7 g, 5.71 mmol, 93.6%yield, 100.0% purity) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.43 (d, J=8.2 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.45 (dd, J=2.0,8.2 Hz, 1H), 5.47 (s, 2H); ES-LCMS m/z 298.0, 300.0 [M+H]⁺.

Step 2: 5-Bromo-2-iodo-N-[3-(trifluoromethyl)phenyl]an

To a solution of 5-bromo-2-iodo-aniline (540 mg, 1.81 mmol, 1 eq) in DCM(8 mL) was added Cu(OAc)₂ (658.44 mg, 3.63 mmol, 2 eq), DIEA (702.77 mg,5.44 mmol, 947.13 μL, 3 eq) and [3-(trifluoromethyl)phenyl]boronic acid(516.39 mg, 2.72 mmol, 1.5 eq). The mixture was stirred at 25° C. for 36h under oxygen atmosphere (15 Psi). TLC (PE/EtOAc=5/1, R_(f)=0.71)indicated starting material was consumed completely and many new spotsformed. The mixture was concentrated and water (80 mL) was added. Themixture was extracted with DCM (50 mL×3). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (From PE/EtOAc=1/0 to 5/1, R_(f)=0.71) to yield5-bromo-2-iodo-N-[3-(trifluoromethyl)phenyl]aniline (650 mg, 1.04 mmol,57.5% yield, 70.9% purity) as red oil. ¹H NMR (400 MHz, CDCl₃) δ ppm7.64-7.61 (m, 1H), 7.48-7.42 (m, 1H), 7.35-7.29 (m, 3H), 7.27 (d, J=2.0Hz, 1H), 6.81 (dd, J=2.2, 8.4 Hz, 1H), 5.98 (s, 1H); ES-LCMS m/z 441.7,443.7 [M+H]⁺.

Step 3:5-Bromo-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of 5-bromo-2-iodo-N-[3-(trifluoromethyl)phenyl]aniline(600 mg, 962.42 μmol, 1 eq) in DMF (20 mL) were addedtributyl-(1-methylimidazol-4-yl)stannane (1.07 g, 1.15 mmol, 1.2 eq) andPd(PPh₃)₄ (111.21 mg, 96.24 μmol, 0.1 eq). The mixture was stirred underN₂ atmosphere at 120° C. for 12 h. The mixture was quenched by sat. aq.KF (50 mL). Water (80 mL) was added and the mixture was extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated to yield a residuewhich was purified by flash silica gel chromatography (from PE/EtOAc=1/0to 5/1, R_(f)=0.39) to yield5-bromo-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline(350 mg, 836.56 μmol, 86.9% yield, 94.7% purity) as red oil. ¹H NMR (400MHz, CDCl₃) δ ppm 10.19 (s, 1H), 8.00 (s, 1H), 7.49-7.44 (m, 2H),7.41-7.34 (m, 3H), 7.29 (d, J=8.3 Hz, 1H), 7.18-7.13 (m, 2H), 6.94 (dd,J=2.0, 8.1 Hz, 1H), 3.73 (s, 3H); ES-LCMS m/z 396.1, 398.1 [M+H]⁺.

Step 4:2-(1-Methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline

To a solution of5-bromo-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline(350 mg, 836.56 μmol, 1 eq) in 1,4-dioxane (12 mL) and H₂O (4 mL) wasadded 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (193.26 mg, 1.25mmol, 212.85 μL, 1.5 eq) Cs₂CO₃ (545.14 mg, 1.67 mmol, 2 eq) andPd(dppf)Cl₂ (48.97 mg, 66.93 μmol, 0.08 eq). The mixture was stirredunder N₂ atmosphere at 100° C. for 12 h. The mixture was concentratedand water (80 mL) was added. The mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=1/0 to 5/1,R_(f)=0.33) to yield2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline(250 mg, 632.02 μmol, 75.6% yield, 86.8% purity) as red oil. ¹H NMR (400MHz, CDCl₃) δ ppm 10.03 (s, 1H), 7.48 (s, 1H), 7.45-7.40 (m, 3H),7.39-7.29 (m, 2H), 7.15 (d, J=1.2 Hz, 1H), 7.10 (d, J=7.3 Hz, 1H), 6.95(dd, J=1.5, 8.1 Hz, 1H), 6.64 (dd, J=10.8, 17.6 Hz, 1H), 5.68 (d, J=17.6Hz, 1H), 5.20 (d, J=10.8 Hz, 1H), 3.73 (s, 3H); ES-LCMS m/z 344.6[M+H]⁺.

Step 5:5-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]anilineand5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline

To a solution of2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]-5-vinyl-aniline(250 mg, 632.02 μmol, 1 eq) in EtOAc (15 mL) was added NaHCO₃ (530.96mg, 6.32 mmol, 10 eq) and dibromomethanone oxime (166.65 mg, 821.62μmol, 1.3 eq). The mixture was stirred under N₂ atmosphere at 25° C. for14 h. The mixture was concentrated and water (80 mL) was added. Themixture was extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 5/1, R_(f)=0.34) to yield peak 1and peak 2. Peak 1 was concentrated under reduced pressure to yield aresidue which was purified by preparative HPLC (column: Agela DuraShellC18 150*25 mm*5 um; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 55%-85%, 10 min). The desired fraction wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline(40.38 mg, 86.79 μmol, 13.7% yield, 100.0% purity, SFC: R_(t)=2.420,ee=99.97%, [α]^(24.9) _(D)=+140 (MeOH, c=0.020 g/100 mL)) as a lightblue solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.15 (s, 1H), 7.50-7.45 (m,2H), 7.39 (s, 1H), 7.38-7.31 (m, 3H), 7.17 (d, J=1.2 Hz, 1H), 7.13 (d,J=6.1 Hz, 1H), 6.84 (dd, J=1.3, 7.9 Hz, 1H), 5.58 (dd, J=9.0, 10.8 Hz,1H), 3.74 (s, 3H), 3.57 (dd, J=10.9, 17.2 Hz, 1H), 3.19 (dd, J=9.0, 17.4Hz, 1H); ES-LCMS m/z 465, 467.0 [M+H]⁺.

Peak 1 was concentrated under reduced pressure to yield a residue whichwas purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5 um; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %:55%-85%, 10 min). The desired fraction was concentrated under reducedpressure to yield a residue which was dissolved in MeCN (20 mL) and H₂O(40 mL) and lyophilized to yield5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[3-(trifluoromethyl)phenyl]aniline(18.82 mg, 40.45 μmol, 6.4% yield, 100.0% purity, SFC: R_(t)=3.024,ee=99.84%, [α]^(24.9) _(D)=−180 (MeOH, c=0.020 g/100 mL)) as a lightblue solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.15 (s, 1H), 7.51-7.44 (m,2H), 7.39 (s, 1H), 7.38-7.30 (m, 3H), 7.17 (d, J=1.0 Hz, 1H), 7.13 (d,J=6.1 Hz, 1H), 6.84 (dd, J=1.3, 7.9 Hz, 1H), 5.58 (dd, J=9.2, 10.6 Hz,1H), 3.74 (s, 3H), 3.57 (dd, J=10.9, 17.2 Hz, 1H), 3.19 (dd, J=9.0, 17.4Hz, 1H); ES-LCMS m/z 464.8, 466.8 [M+H]⁺.

I-262 & I-264

Step 1: Methyl quinoline-3-carboxylate

To a solution of quinoline-3-carboxylic acid (8.80 g, 50.82 mmol, 1 eq)in MeOH (150 mL) was added SOCl₂ (30.23 g, 254.09 mmol, 18.43 mL, 5 eq)dropwise at 0° C. The mixture was stirred at 80° C. for 2 h. TLC(PE/EtOAc=3/1, R_(f)=0.50) showed starting material was consumed and onemajor new spot was detected. The reaction mixture was concentrated,diluted with H₂O (150 mL) and extracted with EtOAc (60 mL×3). Thecombine organic layers were washed with brine (80 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to yield methylquinoline-3-carboxylate (9.5 g, 48.21 mmol, 94.8% yield, 95.0% purity)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (d, J=2.0 Hz,1H), 9.00 (d, J=1.5 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.5 Hz,1H), 7.92 (ddd, J=1.5, 7.0, 8.5 Hz, 1H), 7.75-7.68 (m, 1H), 3.95 (s,3H); ES-LCMS m/z 188.0 [M+H]⁺.

Step 2: Methyl 1,2,3,4-tetrahydroquinoline-3-carboxylate

To a solution of methyl quinoline-3-carboxylate (8.8 g, 44.66 mmol, 1eq) in THF (170 mL) and MeOH (85 mL) was added NaBH₃CN (11.87 g, 188.91mmol, 4.23 eq) and2,6-dibromo-4-[3-(3,5-dibromo-4-hydroxy-2-methyl-phenyl)-1,1-dioxo-2,1benzoxathiol-3-yl]-3-methyl-phenol(4.92 mg, 7.05 μmol, 1.58e-4 eq). The mixture acquired a bluish color(alkaline) at 20° C. Then to the mixture was added HCl/dioxane (4 M, 300mL, 26.87 eq) dropwise slowly to make the mixture obtained yellow color(acid). The mixture was stirred at 80° C. for 12 h. The reaction mixturewas concentrated, diluted with H₂O (100 mL) and extracted with EtOAc(150 mL×3). The combine organic layers were washed with brine (120 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to yield methyl1,2,3,4-tetrahydroquinoline-3-carboxylate (9 g, 42.36 mmol, 94.8% yield,90.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.05-6.97 (m,2H), 6.70-6.63 (m, 1H), 6.52 (dd, J=1.0, 8.4 Hz, 1H), 4.00-3.84 (m, 1H),3.74 (s, 3H), 3.56 (dd, J=3.5, 11.5 Hz, 1H), 3.38 (dd, J=9.5, 11.0 Hz,1H), 3.06-3.00 (m, 2H), 2.98-2.89 (m, 1H); ES-LCMS m/z 192.0 [M+H]⁺.

Step 3: Methyl1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline-3-carboxylate

To a solution of methyl 1,2,3,4-tetrahydroquinoline-3-carboxylate (8.8g, 41.42 mmol, 1 eq) in MeCN (150 mL) was added K₂CO₃ (17.17 g, 124.25mmol, 3 eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (19.80 g,82.83 mmol, 12.61 mL, 2 eq). The mixture was stirred at 80° C. for 12 h.TLC (PE/EtOAc=3/1, R_(f)=0.50) showed the starting material was consumedcompletely and one major new spot was detected. The mixture was dilutedwith H₂O (150 mL) and extracted with EtOAc (150 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to yield methyl1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline-3-carboxylate(14 g, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.63-7.52 (m, 4H), 6.99 (d, J=7.5 Hz, 1H), 6.90 (t, J=7.0 Hz, 1H), 6.54(t, J=7.5 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 4.64-4.51 (m, 2H), 3.62 (s,3H), 3.58-3.45 (m, 2H), 3.12-3.04 (m, 1H), 3.03-2.93 (m, 2H).

Step 4:[1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]methanol

To a solution of methyl1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline-3-carboxylate(14 g, 40.07 mmol, 1 eq) in THE (250 mL) was added LiAlH₄ (6.08 g,160.30 mmol, 4 eq). The mixture was stirred at 20° C. for 2 h. TLC(PE/EtOAc=3/1, R_(f)=0.35) showed starting material was consumedcompletely and one major new spot was detected. H₂O (6 mL), 10% NaOHsolution (6 mL) and H₂O (6 mL) were added slowly to quench the reaction.Na₂SO₄ was added and the mixture was filtered. The filtrate wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from pure PE to PE/EtOAc=5/1, TLC: PE/EtOAc=3/1,R_(f)=0.45) to yield[1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]methanol(11.5 g, 28.63 mmol, 71.5% yield, 80.0% purity) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.67-7.48 (m, 4H), 6.92 (d, J=7.5 Hz, 1H),6.90-6.83 (m, 1H), 6.49 (t, J=7.0 Hz, 1H), 6.43 (d, J=8.5 Hz, 1H), 4.66(t, J=5.5 Hz, 1H), 4.61-4.52 (m, 2H), 3.51-3.34 (m, 3H), 3.13 (dd,J=9.0, 11.0 Hz, 1H), 2.75 (dd, J=3.5, 16.0 Hz, 1H), 2.08 (s, 1H);ES-LCMS m/z 322.3 [M+H]⁺.

Step 5:1-[[3-(Trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline-3-carbaldehyde

To a solution of oxalyl dichloride (7.90 g, 62.24 mmol, 5.45 mL, 5 eq)in DCM (150 mL) was added DMSO (9.73 g, 124.48 mmol, 9.73 mL, 10 eq) inDCM (20 mL) dropwise at −78° C. and stirred under N₂ atmosphere at −78°C. for 0.5 h. To the mixture was added[1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-3-yl]methanol(5 g, 12.45 mmol, 1 eq) in DCM (20 mL) dropwise at −78° C. The reactionmixture was stirred under N₂ atmosphere at −78° C. for 0.5 h. To themixture was added DIEA (16.09 g, 124.48 mmol, 21.68 mL, 10 eq) in DCM(10 mL) dropwise at −78° C. The mixture was stirred under N₂ atmosphereat 20° C. for 11 h. TLC (PE/EtOAc=3/1, R_(f)=0.60) showed startingmaterial was consumed and one major new spot was detected. The mixturewas diluted with H₂O (150 mL) and extracted with DCM (150 mL×3). Thecombine organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to yield1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline-3-carbaldehyde(10 g, crude) as yellow oil, which was used in the next step withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.74 (s, 1H),7.50-7.44 (m, 3H), 7.37-7.34 (m, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.98-6.93(m, 1H), 6.65-6.60 (m, 1H), 6.47-6.42 (m, 1H), 4.51-4.48 (m, 2H),3.77-3.72 (m, 1H), 3.41 (t, J=4.0 Hz, 1H), 3.07-3.00 (m, 3H); ES-LCMSm/z 320.1 [M+H]⁺.

Step 6:(3R)-1-[[3-(Trifluoromethyl)phenyl]methyl]-3-vinyl-3,4-dihydro-2H-quinolineand(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-vinyl-3,4-dihydro-2H-quinoline

To a solution of methyl(triphenyl)phosphonium; bromide (16.7 g, 46.75mmol, 1.49 eq) in THF (30 mL) was added n-BuLi (2.5 M, 18 mL, 1.44 eq).The mixture was stirred under N₂ atmosphere at −78° C. for 0.5 h. To themixture was added1-[[3-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-2H-quinoline-3-carbaldehyde(10 g, 31.32 mmol, 1 eq) in THF (2 mL). The mixture was stirred under N₂atmosphere at 20° C. for 4.5 h. TLC (PE/EtOAc=5/1, R_(f)=0.50) showedstarting material was consumed completely and one major new spot wasdetected. The mixture was quenched with sat. aq. NH₄Cl (200 mL) andextracted with EtOAc (200 mL×3). The combine organic layers were washedwith brine (80 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (from pure PE to PE/EtOAc=50/1, TLC: PE/EtOAc=5/1,R_(f)=0.50) to yield a residue which was purified by preparative HPLC(HCl condition; column: Agela ASB 150*25 mm*5 μm; mobile phase: [water(0.05% HCl)-ACN]; B %: 65%-95%, 8 min) and lyophilized to yield aresidue which was separated by preparative SFC (column: DAICEL CHIRALCELOD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B %:10%-10%, min) to yield Peak 1 and Peak 2. Peak 1 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (20 mL)and H₂O (40 mL) and lyophilized to yield(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-vinyl-3,4-dihydro-2H-quinoline(410 mg, 1.29 mmol, 50.6% yield, 100.0% purity, SFC: R_(t)=2.448,ee=77.48%, [α]^(22.7) _(D)=−8.810 (MeOH, c=0.048 g/100 mL) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64-7.51 (m, 4H), 6.95 (d, J=7.6Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 6.50 (t, J=7.6 Hz, 1H), 6.43 (d, J=8.0Hz, 1H), 5.88 (ddd, J=6.0, 10.8, 16.8 Hz, 1H), 5.22-5.03 (m, 2H),4.69-4.51 (m, 2H), 3.41 (d, J=12.8 Hz, 1H), 3.25-3.16 (m, 1H), 2.89-2.78(m, 1H), 2.73-2.63 (m, 2H); ES-LCMS m/z 318.4 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-vinyl-3,4-dihydro-2H-quinoline(410 mg, 1.29 mmol, 50.6% yield, 100.0% purity, SFC: R_(t)=2.560,ee=91.28%, [α]^(22.7) _(D)=+3.878 (MeOH, c=0.051 g/100 mL) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.64-7.52 (m, 4H), 6.95 (d, J=7.2Hz, 1H), 6.89 (t, J=7.6 Hz, 1H), 6.50 (t, J=7.2 Hz, 1H), 6.43 (d, J=8.4Hz, 1H), 5.88 (ddd, J=5.6, 10.8, 17.2 Hz, 1H), 5.22-5.04 (m, 2H),4.68-4.50 (m, 2H), 3.41 (d, J=13.2 Hz, 1H), 3.26-3.17 (m, 1H), 2.89-2.79(m, 1H), 2.74-2.63 (m, 2H); ES-LCMS m/z 318.2 [M+H]⁺.

Step 7:(5S)-3-bromo-5-methyl-5-[(3R)-3-methyl-1-[[3-(trifluoromethyl)phenyl]methyl]-2,4-dihydroquinolin-3-yl]-4H-isoxazole

To a solution of(3S)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-vinyl-3,4-dihydro-2H-quinoline(200 mg, 630.22 μmol, 1 eq) in EtOAc (5 mL) was added NaHCO₃ (529.45 mg,6.30 mmol, 10 eq) and dibromomethanone oxime (221.15 mg, 1.09 mmol, 1.73eq). The mixture was stirred at 15° C. for 12 h. TLC (PE/EtOAc=3/1,R_(f)=0.40) showed starting material was consumed completely and onemajor new spot was detected. The mixture was diluted with H₂O (20 mL)and extracted with EtOAc (20 mL×3). The combine organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated to yield aresidue which was purified by flash silica gel chromatography (from purePE to PE/EtOAc=5/1, TLC: PE/EtOAc=3/1, R_(f)=0.40) to yield a residuewhich was separated by preparative SFC (column: DAICEL CHIRALPAK IG (250mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 25%-25%) toyield Peak 1 and Peak 2. Peak 2 was concentrated under reduced pressureto yield a residue which was dissolved in MeCN (20 mL) and H₂O (40 mL)and lyophilized to yield(5S)-3-bromo-5-methyl-5-[(3R)-3-methyl-1-[[3-(trifluoromethyl)phenyl]methyl]-2,4-dihydroquinolin-3-yl]-4H-isoxazole(37.19 mg, 79.58 μmol, 12.6% yield, 100.0% purity, SFC: R_(t)=2.808,ee=95.24%, [α]^(25.2) _(D)=+77.358 (MeOH, c=0.080 g/100 mL) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.56-7.50 (m, 2H), 7.48-7.41 (m,2H), 7.09-7.00 (m, 2H), 6.71-6.66 (m, 1H), 6.53 (d, J=8.0 Hz, 1H),4.77-4.68 (m, 1H), 4.57-4.47 (m, 2H), 3.35-3.28 (m, 1H), 3.28-3.19 (m,2H), 3.06-2.93 (m, 2H), 2.90-2.80 (m, 1H), 2.42-2.32 (m, 1H); ES-LCMSm/z 439.0, 441.0 [M+H]⁺.

Step 8:(5R)-3-Bromo-5-methyl-5-[(3S)-3-methyl-1-[[3-(trifluoromethyl)phenyl]methyl]-2,4-dihydroquinolin-3-yl]-4H-isoxazole

To a solution of(3R)-1-[[3-(trifluoromethyl)phenyl]methyl]-3-vinyl-3,4-dihydro-2H-quinoline(200 mg, 630.22 μmol, 1 eq) in EtOAc (1 mL) was added NaHCO₃ (529.45 mg,6.30 mmol, 10 eq) and dibromomethanone oxime (199.41 mg, 983.15 μmol,1.56 eq). The mixture was stirred at 15° C. for 12 h. The mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combineorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to yield a residue which was purified by flash silica gelchromatography (from pure PE to PE/EtOAc=5/1, TLC: PE/EtOAc=3/1,R_(f)=0.40). The desired fraction was concentrated under reducedpressure to yield a residue which was separated by preparative SFC(column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1%NH₃H₂O EtOH]; B %: 30%-30%) to yield Peak 1 and Peak 2. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasseparated by preparative SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm,10 μm); mobile phase: [0.1% NH₃H₂O MeOH]; B %: 35%-35%) to yield Peak 3.Peak 3 was concentrated under reduced pressure to yield a residue whichwas dissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield(5R)-3-bromo-5-methyl-5-[(3S)-3-methyl-1-[[3-(trifluoromethyl)phenyl]methyl]-2,4-dihydroquinolin-3-yl]-4H-isoxazole(37.95 mg, 81.21 μmol, 12.9% yield, 100.0% purity, SFC1: R_(t)=4.662,ee=100%, SFC2: R_(t)=3.802, ee=100%, [α]^(25.1) _(D)=−86.276 (MeOH,c=0.093 g/100 mL) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm7.57-7.49 (m, 2H), 7.49-7.41 (m, 2H), 7.09-6.99 (m, 2H), 6.72-6.65 (m,1H), 6.53 (d, J=8.0 Hz, 1H), 4.79-4.66 (m, 1H), 4.59-4.44 (m, 2H),3.35-3.28 (m, 1H), 3.28-3.18 (m, 2H), 3.06-2.93 (m, 2H), 2.89-2.80 (m,1H), 2.43-2.30 (m, 1H); ES-LCMS m/z 438.8, 440.8 [M+H]⁺.

I-265 & I-266

Step 1: (5R)-3-Bromo-5-[1-[[4-(trifluoromethylsμLfanyl)

To a solution of methyl(triphenyl)phosphonium; bromide (9.96 g, 27.89mmol, 1.3 eq) in THF (80 mL) was added n-BuLi (2.5 M, 11.16 mL, 1.3 eq)dropwise under N₂ atmosphere at −65° C. The mixture was stirred under N₂atmosphere at 0° C. for 0.5 h. The mixture was cooled to −70° C. and asolution of tert-butyl (3R)-3-formylpyrrolidine-1-carboxylate (4.5 g,21.46 mmol, 1 eq) in THE (20 mL) was added slowly. The mixture wasstirred under N₂ atmosphere at 20° C. for 4 h. TLC (PE/EtOAc=10/1,R_(f)=0.70) indicated starting material was consumed completely and onenew spot formed. The reaction mixture was quenched by addition ofsaturated aqueous NH₄C₁ (20 mL) and water (500 mL) and extracted withEtOAc (500 mL×3). The combined organic layers were washed with brine(200 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 20/1, TLC: PE/EtOAc=10/1,R_(f)=0.70) to yield tert-butyl (3S)-3-vinylpyrrolidine-1-carboxylate(3.5 g, 15.97 mmol, 74.4% yield, 90.0% purity) as colorless oil. ¹H NMR(500 MHz, CDCl₃) δ ppm 5.84-5.66 (m, 1H), 5.08 (d, J=17.1 Hz, 1H), 5.01(d, J=10.4 Hz, 1H), 3.58-3.37 (m, 2H), 3.32-3.20 (m, 1H), 3.09-2.96 (m,1H), 2.79-2.70 (m, 1H), 2.02-1.94 (m, 1H), 1.71-1.63 (m, 1H), 1.44 (s,9H).

Step 2: tert-Butyl(3R)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]pyrrolidine-1-carboxylateand tert-butyl(3R)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]pyrrolidine-1-carboxylate

To a solution of tert-butyl (3S)-3-vinylpyrrolidine-1-carboxylate (2.9g, 13.23 mmol, 1 eq) in EtOAc (50 mL) was added NaHCO₃ (8.89 g, 105.84mmol, 4.12 mL, 8 eq) and dibromomethanone oxime (2.82 g, 13.89 mmol,1.05 eq). The mixture was stirred at 20° C. for 12 h. TLC (PE/EtOAc=3/1,R_(f)=0.31, 0.29) indicated starting material was consumed completelyand one new spot formed. The reaction mixture was quenched by additionof water (100 mL) and extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine (400 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (from PE/EtOAc=1/0to 17/3, TLC: PE/EtOAc=3/1, R_(f)=0.31, 0.29) to yield fraction 1 andfraction 2. Fraction 1 was concentrated under reduced pressure to yieldtert-butyl(3R)-3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]pyrrolidine-1-carboxylate(1.2 g, 3.76 mmol, 28.4% yield, 100.0% purity, SFC: R_(t)=2.362,ee=94.5%; [α]^(23.7) _(D)=−57.6 (MeOH, c=0.250 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.70-4.52 (m, 1H), 3.62-3.41 (m,2H), 3.34-3.27 (m, 2H), 3.13-2.99 (m, 1H), 2.97-2.84 (m, 1H), 2.48-2.41(m, 1H), 2.11-2.03 (m, 1H), 1.91-1.68 (m, 1H), 1.45 (s, 9H). ES-LCMS m/z262.9, 264.9 [M-t-Bu+H]⁺. Fraction 2 was concentrated under reducedpressure to yield tert-butyl(3R)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]pyrrolidine-1-carboxylate(1.1 g, 3.45 mmol, 26.1% yield, 100.0% purity, SFC: R_(t)=2.009,ee=95.4%; [α]^(23.7) _(D)=+88.1 (MeOH, c=0.270 g/100 mL)) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.71-4.50 (m, 1H), 3.65-3.55 (m,1H), 3.54-3.41 (m, 1H), 3.33-3.28 (m, 2H), 3.20 (dd, J=8.5, 10.6 Hz,1H), 2.96-2.91 (m, 1H), 2.49-2.41 (m, 1H), 1.99-1.88 (m, 1H), 1.71-1.64(m, 1H), 1.45 (s, 9H).

Step 3: (5S)-3-Bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3R)-3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]pyrrolidine-1-carboxylate(700 mg, 1.97 mmol, 1 eq) in DCM (10 mL) was added TFA (2.10 mL, 28.36mmol, 14.37 eq). The mixture was stirred at 20° C. for 2 h. TLC(PE/EtOAc=3/1, R_(f)=0) indicated starting material was consumedcompletely and one new spot formed. The reaction mixture wasconcentrated to yield(5S)-3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (700 mg, 1.89mmol, 95.8% yield, 90.0% purity, TFA) as yellow oil. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 4.68 (d, J=8.1, 10.4 Hz, 1H), 3.47 (dd, J=10.5, 17.5 Hz,1H), 3.36-3.30 (m, 1H), 3.28-3.23 (m, 1H), 3.20-3.10 (m, 2H), 3.00-2.89(m, 1H), 2.60-2.54 (m, 1H), 2.10-2.01 (m, 1H), 1.60 (d, J=8.3, 13.0 Hz,1H) 1.34 (s, 1H).

Step 4:(5S)-3-Bromo-5-[(3R)-1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]pyrrolidin-3-yl]-4,5-dihydroisoxazoleand(5S)-3-bromo-5-[(3R)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a solution of(5S)-3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole (300 mg,810.56 μmol, 1 eq, TFA) in MeOH (0.5 mL) and Ti(i-PrO)₄ (2 mL) was added1-[4-(trifluoromethyl)phenyl]ethanone (198.26 mg, 1.05 mmol, 1.3 eq),DIEA (314.27 mg, 2.43 mmol, 423.55 μL, 3 eq) and the mixture was stirredat 80° C. for 2 h. The reaction mixture was cooled to 15° C. MeOH (30mL) and NaBH₃CN (254.68 mg, 4.05 mmol, 5 eq) were added and the mixturewas stirred at 50° C. for 12 h. The reaction mixture was quenched byaddition of 15% NaOH (5 mL) and water (50 mL) and extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine (40 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toyield a residue which was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 um; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 53%-83%, 10 min) to yield the compound which wasseparated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um);mobile phase: [0.1% NH₃H₂O/MeOH]; B %: 30%-30%) to yield peak 1 and peak2. Peak 1 was concentrated under reduced pressure to yield(5S)-3-bromo-5-[(3R)-1-[(1R)-1-[4-(trifluoromethyl)phenyl]ethyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(19.01 mg, 46.11 μmol, 5.7% yield, 94.9% purity, SFC: R_(t)=2.166,ee=100%, [α]²⁴0.0_(D)=+99.1 (MeOH, c=0.063 g/100 mL)) as a white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 7.56 (d, J=7.8 Hz, 2H), 7.42 (d, J=8.2 Hz,2H), 4.67-4.56 (m, 1H), 3.31-3.18 (m, 2H), 2.96 (dd, J=8.6, 17.2 Hz,1H), 2.76-2.61 (m, 2H), 2.51-2.33 (m, 3H), 2.02-1.88 (m, 1H), 1.46 (dd,J=6.7, 12.9 Hz, 1H), 1.37 (d, J=6.3 Hz, 3H); ES-LCMS m/z 391.0, 393.0[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield(5S)-3-bromo-5-[(3R)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]pyrrolidin-3-yl]-4,5-dihydroisoxazole(24.29 mg, 59.36 μmol, 7.3% yield, 95.6% purity, SFC: R_(t)=3.155,ee=95.4%, [α]^(24.0) _(D)=+46.5 (MeOH, c=0.051 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.56 (d, J=7.8 Hz, 2H), 7.43 (d,J=7.8 Hz, 2H), 4.66 (q, J=8.9 Hz, 1H), 3.24 (dd, J=10.4, 17.0 Hz, 2H),2.90 (dd, J=8.2, 17.2 Hz, 1H), 2.62-2.50 (m, 3H), 2.49-2.42 (m, 2H),1.97 (s, 1H), 1.45-1.39 (m, 1H), 1.36 (d, J=6.3 Hz, 3H); ES-LCMS m/z391.0, 393.0 [M+H]⁺.

I-275

Step 1: 2-(Chloromethyl)-5-(trifluoromethyl)pyridine

To a solution of [5-(trifluoromethyl)-2-pyridyl]methanol (200 mg, 1.13mmol, 155.04 μL, 1 eq) in DCM (3 mL) was added SOCl₂ (403.01 mg, 3.39mmol, 245.74 μL, 3 eq). The mixture was stirred at 50° C. for 2 h. Thereaction mixture was concentrated under reduced pressure to yield2-(chloromethyl)-5-(trifluoromethyl)pyridine (200 mg, 971.52 μmol, 86.0%yield, 95.0% purity) as yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.97(s, 1H), 8.28 (dd, J=2.1, 8.2 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 4.90 (s,2H).

Step 2:(5R)-3-Bromo-5-[1-[[5-(trifluoromethyl)-2-pyridyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 2-(chloromethyl)-5-(trifluoromethyl)pyridine (73.68 mg,357.93 μmol, 95% purity, 1 eq) in DMF (2 mL) was added DIEA (138.78 mg,1.07 mmol, 187.03 μL, 3 eq) and(5R)-3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (87.83 mg, 357.93μmol, 95% purity, 1 eq). The mixture was stirred under N₂ atmosphere at15° C. for 2 h. The reaction mixture was quenched by addition of water(20 mL) and extracted with EtOAc (20 mL×3). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield a residue which waspurified by preparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4um; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%, 9 min). Thedesired fraction was basified with saturated NaHCO₃ (20 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, concentrated under reducedpressure and lyophilized to yield(5R)-3-bromo-5-[1-[[5-(trifluoromethyl)-2-pyridyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(17.48 mg, 44.03 μmol, 12.3% yield, 98.8% purity, [α]^(25.1) _(D)=−89.9(MeOH, c=0.0356 g/100 mL)) as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm 8.81 (s, 1H), 7.89 (dd, J=1.8, 8.0 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H),4.61-4.44 (m, 1H), 3.71 (s, 2H), 3.24-3.06 (m, 1H), 2.99-2.88 (m, 3H),2.15-2.04 (m, 2H), 1.85 (d, J=13.3 Hz, 1H), 1.71-1.58 (m, 2H), 1.49-1.35(m, 2H); ES-LCMS m/z 392.1, 394.1 [M+H]⁺.

I-276

Step 1: 1-(Bromomethyl)-4-(trifluoromethylsulfonyl)benzene

To a solution of 1-(bromomethyl)-4-(trifluoromethylsulfanyl)benzene (500mg, 1.84 mmol, 1 eq) in DCM (15 mL) was added m-CPBA (1.87 g, 9.22 mmol,85% purity, 5 eq). The mixture was stirred at 40° C. for 24 h. Thereaction mixture was concentrated to yield a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=1/0 to 11/1, TLC:PE/EtOAc=3/1, R_(f)=0.65) to yield1-(bromomethyl)-4-(trifluoromethylsulfonyl)benzene (499 mg, 1.65 mmol,89.3% yield, 100.0% purity) as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm 8.03 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.6 Hz, 2H), 4.54 (s, 2H).

Step 2:(5R)-3-Bromo-5-[1-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of (5R)-3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (50mg, 197.76 μmol, 92.2% purity, 1 eq) in DMF (2 mL) was added1-(bromomethyl)-4-(trifluoromethylsulfonyl)benzene (59.94 mg, 197.76μmol, 100% purity, 1 eq) and DIEA (51.12 mg, 395.53 μmol, 68.89 μL, 2eq). The mixture was stirred at 20° C. for 16 h. The reaction mixturewas concentrated to yield a residue which was purified by preparativeHPLC (column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water(0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 50%-80%, 10 min), followed bylyophilization to yield(5R)-3-bromo-5-[1-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(8.12 mg, 17.48 μmol, 8.8% yield, 98.0% purity) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.99 (d, J=7.8 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H),4.54-4.47 (m, 1H), 3.62 (s, 2H), 3.21 (dd, J=10.6, 17.2 Hz, 1H),3.00-2.87 (m, 3H), 2.07-1.99 (m, 2H), 1.86 (d, J=13.3 Hz, 1H), 1.64 (s,2H), 1.46-1.36 (m, 2H); ES-LCMS m/z 455, 457.0 [M+H]⁺.

I-279

Step 1:(5R)-3-Bromo-5-[1-[[2-methyl-4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of (5R)-3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (50mg, 132.80 μmol, 92.2%, 1 eq, TFA) in MeOH (2 mL) was added2-methyl-4-(trifluoromethyl)benzaldehyde (37.48 mg, 199.21 μmol, 1.5 eq)and DIEA (85.82 mg, 664.02 μmol, 115.66 μL, 5 eq) at 50° C. Afteraddition, the mixture was stirred at this temperature for 2 h. NaBH₃CN(33.38 mg, 531.22 μmol, 4 eq) was added partwise at 15° C. The resultingmixture was stirred at 15° C. for 2 h. The solvent was removed to yielda residue which was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 63%-93%, 10 min) and lyophilized to yield(5R)-3-bromo-5-[1-[[2-methyl-4-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(4.31 mg, 10.17 μmol, 7.7% yield, 95.6% purity, [α]^(19.5) _(D)=−60.0(MeOH, c=0.002 g/100 mL)) as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm 7.40 (s, 3H), 4.53-4.45 (m, 1H), 3.47 (s, 2H), 3.19 (dd, J=10.5,17.1 Hz, 1H), 2.96 (dd, J=9.0, 17.1 Hz, 3H), 2.40 (s, 3H), 2.09-1.94 (m,2H), 1.83 (d, J=11.7 Hz, 1H), 1.68-1.61 (m, 1H), 1.44-1.24 (m, 3H);ES-LCMS m/z 405.1, 407.1 [M+H]⁺.

I-290

Step 1: Piperidin-4-one

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10.04mmol, 1 eq) in DCM (10 mL) was added TFA (2 mL). The mixture was stirredat 20° C. for 1 h. TLC (DCM/MeOH=10/1, R_(f)=0.6) indicated the startingmaterial was consumed completely and one new spot formed. The reactionmixture was concentrated to yield piperidin-4-one (1.82 g, 5.98 mmol,59.5% yield, 70.0% purity, TFA) as yellow oil which was used in the nextstep without further purification. ¹H NMR (500 MHz, CD₃OD) δ ppm3.25-3.20 (m, 4H), 1.99-1.90 (m, 4H).

Step 2: 1-Prop-2-enoylpiperidin-4-one

To a solution of piperidin-4-one (1 g, 3.28 mmol, 70% purity, 1 eq, TFA)and DIEA (848.85 mg, 6.57 mmol, 1.14 mL, 2 eq) in DCM (5 mL) was added asolution of prop-2-enoyl chloride (594.46 mg, 6.57 mmol, 535.55 μL, 2eq) in DCM (2 mL). The mixture was stirred at 0° C. for 30 min. TLC(DCM/MeOH=10/1, R_(f)=0.8) indicated the starting material was consumedcompletely and three new spots formed. The reaction mixture wasconcentrated to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 1/2, TLC: DCM/MeOH=10/1, R_(f)=0.8)to yield 1-prop-2-enoylpiperidin-4-one (190 mg, 1.12 mmol, 34.0% yield,90.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.63 (dd,J=10.4, 16.8 Hz, 1H), 6.36 (d, J=16.8, 1H), 5.77 (dd, J=1.6, 10.4 Hz,1H), 3.93-3.85 (m, 4H), 2.52-2.49 (m, 4H).

Step 3:1-[4-[[(1S)-1-[4-(Trifluoromethyl)phenyl]ethyl]amino]-1-piperidyl]prop-2-en-1-one

A mixture of 1-prop-2-enoylpiperidin-4-one (80 mg, 470.04 μmol, 90%purity, 1 eq) and (1S)-1-[4-(trifluoromethyl)phenyl]ethanamine (106.06mg, 470.04 μmol, 1 eq, HCl) in DCE (5 mL) was stirred at 40° C. for 16h. NaBH₃CN (118.15 mg, 1.88 mmol, 4 eq) was added and the mixture wasstirred at 40° C. for 1 h. The solvent was removed to yield a residuewhich was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 um; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN];B %: 33%-63%, 10 min) to yield1-[4-[[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]amino]-1-piperidyl]prop-2-en-1-one(110.68 mg, 339.14 μmol, 72.2% yield, 100.0% purity, [α]^(22.4)_(D)=−60.13 (MeOH, c=0.193 g/100 mL)) as a white solid. ¹H NMR (500 MHz,CD₃OD) δ ppm 7.68-7.62 (m, 2H), 7.58 (d, J=8.1 Hz, 2H), 6.75 (ddd,J=6.3, 10.6, 16.8 Hz, 1H), 6.17 (d, J=16.8 Hz, 1H), 5.72 (dd, J=1.9,10.6 Hz, 1H), 4.46 (t, J=15.1 Hz, 1H), 4.13-4.00 (m, 2H), 3.10-2.96 (m,1H), 2.74-2.60 (m, 1H), 2.58-2.49 (m, 1H), 2.05 (d, J=13.0 Hz, 1H), 1.81(d, J=12.8 Hz, 1H), 1.38 (d, J=6.7 Hz, 3H), 1.35-1.22 (m, 2H); ES-LCMS mz 327.1 [M+H]⁺.

I-298

Step 1:2-[4-4(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid

To a solution of methyl2-[4-[(R)—3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceate(150 mg, 333.88 mol, 100% purity, 1 eq) in i-PrOH (1.5 mL), water (1.5mL) and THE (1.5 mL) were added LiOH (23.99 mg, 1.00 mmol, 3 eq). Themixture was stirred under N₂ atmosphere at 70° C. for 1 h. The mixturewas adjusted pH to 5-6 with 2 N HCL. The reaction mixture wasconcentrated under reduced pressure to yield2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid (145 mg, 319.49 mol, 95.700 yield, 95.9% purity) as a white solid,which was used in the next step without further purification. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.57 (s, 4H), 4.42 (d, J=8.6 Hz, 1H), 3.65 (s,1H), 3.35-3.23 (m, 4H), 3.08-2.98 (m, 1H), 2.55 (d, J=11.3 Hz, 1H),1.81-1.52 (m, 2H), 1.30-1.11 (m, 2H), 1.04-1.00 (in, 1H); ES-LCMS m/z434.8, 436.8 [M+H]⁺.

Step 2:2-[4-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetamide

To a solution of2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid (45 mg, 98.22 μmol, 95% purity, 1 eq) in DMF (2 mL) was added NH₄Cl(15.76 mg, 294.67 μmol, 3 eq), DIEA (63.47 mg, 491.11 μmol, 85.54 μL, 5eq) and HATU (74.69 mg, 196.45 μmol, 2 eq). The mixture was stirredunder N₂ atmosphere at 50° C. for 2 h. The reaction mixture was purifiedby preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 36%-66%, 10 min) to yield2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetamide(16.18 mg, 37.26 μmol, 37.9% yield, 100.0% purity, [α]^(21.3) _(D)=−68(MeOH, c=0.1 g/100 mL)) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm7.66-7.61 (m, 4H), 4.54-4.43 (m, 1H), 3.90 (s, 1H), 3.29-3.22 (m, 1H),3.14 (d, J=11.3 Hz, 1H), 3.04 (ddd, J=4.7, 8.8, 17.4 Hz, 1H), 2.68 (d,J=11.7 Hz, 1H), 2.17-2.05 (m, 1H), 1.87-1.68 (m, 2H), 1.63-1.45 (m, 3H),1.44-1.28 (m, 1H); ES-LCMS m/z 434.1, 436.1 [M+H]⁺.

I-299

Step 1:(2S)-2-[4-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-N-methyl-2-[4-(trifluoromethyl)phenyl]acetamide

To a stirred solution of(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid (50 mg, 114.88 μmol, 1 eq) and methanamine (23.27 mg, 344.64 μmol,3 eq, HCl) in DMF (3 mL) was added HATU (87.36 mg, 229.76 μmol, 2 eq)and DIEA (74.24 mg, 574.40 μmol, 100.05 μL, 5 eq). The reaction mixturewas stirred at 70° C. for 1 h. The reaction mixture was filtered and thefiltrate was purified by preparative HPLC (column: Welch Xtimate C18150*25 mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 35%-65%,10 min). The desired fraction was lyophilized to yield(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-N-methyl-2-[4-(trifluoromethyl)phenyl]acetamide(23.38 mg, 52.16 μmol, 45.4% yield, 100.0% purity, [α]^(21.5) _(D)=−81.6(MeOH, c=0.125 g/100 mL)) as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm 7.62 (q, J=8.3 Hz, 4H), 4.57-4.43 (m, 1H), 3.88 (s, 1H), 3.30-3.22(m, 1H), 3.10-2.97 (m, 2H), 2.74 (s, 3H), 2.66 (d, J=11.0 Hz, 1H),2.18-2.02 (m, 1H), 1.86-1.66 (m, 2H), 1.65-1.45 (m, 3H), 1.45-1.32 (m,1H); ES-LCMS m/z 448.0, 450.0 [M+H]⁺.

I-300

Step 1:2-[4-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-N-methyl-2-[4-(trifluoromethyl)phenyl]acetamide

To a solution of2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid (50 mg, 109.14 μmol, 95% purity, 1 eq) in DMF (3 mL) was added HATU(82.99 mg, 218.27 μmol, 2 eq), DIEA (70.52 mg, 545.68 μmol, 95.05 μL, 5eq) and methanamine (22.11 mg, 327.41 μmol, 3 eq, HCl). The mixture wasstirred under N₂ atmosphere at 50° C. for 2 h. The reaction mixture waspurified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 37%-67%, 10 min) toyield2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-N-methyl-2-[4-(trifluoromethyl)phenyl]acetamide(15.18 mg, 33.86 μmol, 31.0% yield, 100.0% purity, [α]^(23.0) _(D)-100(MeOH, c=0.1 g/100 mL)) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm7.62 (q, J=8.3 Hz, 4H), 4.55-4.45 (m, 1H), 3.88 (s, 1H), 3.30-3.23 (m,1H), 3.10-2.97 (m, 2H), 2.73 (s, 3H), 2.66 (d, J=11.3 Hz, 1H), 2.15-2.04(m, 1H), 1.85-1.67 (m, 2H), 1.64-1.46 (m, 3H), 1.44-1.27 (m, 1H);ES-LCMS m/z 448.1, 450.1 [M+H]⁺.

I-303 & I-304

Step 1: 1-(3-(Trifluoromethyl)phenyl)ethanol

To a solution of 1-[3-(trifluoromethyl)phenyl]ethanone (2.3 g, 12.22mmol, 1.83 mL, 1 eq) in MeOH (20 mL) was added NaBH₄ (508.70 mg, 13.45mmol, 1.1 eq). The mixture was stirred at 18° C. for 1 h. TLC(PE/EtOAc=4/1, R_(f)=0.35) showed the starting material was consumed andone new spot was detected. The mixture was concentrated, diluted withwater (20 mL) and extracted with EtOAc (20 mL×3). The combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to yield 1-[3-(trifluoromethyl)phenyl]ethanol (2.3 g, 12.09mmol, 98.9% yield, 100.0% purity) as yellow oil, which was used in thenext step without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm7.66 (s, 1H), 7.61-7.52 (m, 2H), 7.51-7.44 (m, 1H), 5.06-4.86 (m, 1H),1.91 (d, J=4.4 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H); ES-LCMS m/z 214.3[M+H]⁺.

Step 2: 1-(3-(Trifluoromethyl)phenyl)ethyl methanesulfonate

To a solution of 1-[3-(trifluoromethyl)phenyl]ethanol (1.0 g, 5.26 mmol,1.83 mL, 100% purity, 1 eq) in DCM (10 mL) was added TEA (1.60 g, 15.78mmol, 2.20 mL, 3.0 eq). The mixture was stirred at 15° C. for 10 min.MsCl (0.760 g, 6.63 mmol, 513.51 μL, 1.26 eq) was added into themixture. The mixture was stirred at 15° C. for 50 min. TLC(PE/EtOAc=4/1, R_(f)=0.47) showed the starting material was consumed andone new spot was detected. The mixture was concentrated, diluted withwater (10 mL) and extracted with EtOAc (10 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to yield1-[3-(trifluoromethyl)phenyl]ethyl methanesulfonate (1.4 g, 5.22 mmol,99.2% yield, N/A purity) as yellow oil, which was used in the next stepwithout further purification.

Step 3:(S)-3-Bromo-5-((R)—1-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)piperidin-3-yl)-4,5-dihydroisoxazoleand(S)-3-bromo-5-((R)—1-((R)—1-(3-(trifluoromethyl)phenyl)ethyl)piperidin-3-yl)-4,5-dihydroisoxazole

To a solution of 1-[3-(trifluoromethyl)phenyl]ethyl methanesulfonate(1.38 g, 5.14 mmol, N/A purity, 2.0.0 eq) in DMF (10 mL) was added(5S)-3-bromo-5-[(3R)-3-piperidyl]-4,5-dihydroisoxazole (600 mg, 2.57mmol, N/A purity, 1 eq, TFA), Cs₂CO₃ (2.51 g, 7.72 mmol, 3 eq). Themixture was stirred at 20° C. for 72 h. The mixture was filtered, washedwith DCM (50 mL×2). The filtrate was concentrated to yield a residuewhich was purified by preparative HPLC (column: YMC-Actus Triart C18100*30 mm*5 um; mobile phase: [water (0.1% TFA)-ACN]; B %: 25%-55%, 11min), followed by lyophilization to yield the reside which was purifiedby SFC (column: DAICEL CHIRALPAK AY-H (250 mm*30 mm, Sum); mobile phase:[0.1% NH₃H₂O/IPA]; B %: 15%-15%), followed by lyophilization to yieldpeak 1 and peak 2. Peak 1 was concentrated under reduced pressure toyield a residue which was dissolved in MeCN (20 mL) and H₂O (40 mL) andlyophilized to yield(5S)-3-bromo-5-[(3R)-1-[(1S)-1-[3-(trifluoromethyl)phenyl]ethyl]-3-piperidyl]-4,5-dihydroisoxazole(29.98 mg, 73.98 μmol, 2.9% yield, 100.0% purity, R_(t)=1.513,ee=100.0%, [α]^(25.6) _(D)=+108 (MeOH, c=0.1 g/100 mL) as a white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 7.58-7.48 (m, 3H), 7.47-7.40 (m, 1H), 4.49(q, J=9.3 Hz, 1H), 3.55 (q, J=6.5 Hz, 1H), 3.26-3.12 (m, 2H), 3.06-2.93(m, 1H), 2.70 (d, J=11.0 Hz, 1H), 1.98-1.83 (m, 3H), 1.6-1.52 (m, 3H),1.40 (d, J=6.7 Hz, 3H), 1.10-0.94 (m, 1H); ES-LCMS m/z 405.1, 407.1[M+H]⁺. Peak 2 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (20 mL) and H₂O (40 mL) andlyophilized to yield(S)-3-bromo-5-((R)—1-((R)—1-(3-(trifluoromethyl)phenyl)ethyl)piperidin-3-yl)-4,5-dihydroisoxazole(15.49 mg, 38.22 μmol, 1.5% yield, 100.0% purity, R_(t)=1.988,ee=100.0%, [α]^(25.6) _(D)=+72 (MeOH, c=0.1 g/100 mL) as a white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 7.60-7.39 (m, 4H), 4.53-4.41 (m, 1H), 3.66(s, 1H), 3.17 (dd, J=10.4, 17.0 Hz, 1H), 3.02-2.78 (m, 3H), 2.16-1.86(m, 3H), 1.79-1.54 (m, 3H), 1.42 (d, J=5.1 Hz, 3H), 1.02 (d, J=7.8 Hz,1H); ES-LCMS m/z 405.1, 407.1 [M+H]⁺.

I-305

Step 1: 4-(1,1,2,2,2-Pentafluoroethyl)benzonitrile

To a solution of 4-iodobenzonitrile (1 g, 4.37 mmol, 1 eq) and2,2,3,3,3-pentafluoropropanoyloxysodium (2.11 g, 11.35 mmol, 2.6 eq) inDMF (12 mL) was added CuI (2.16 g, 11.35 mmol, 2.6 eq) under N₂atmosphere. The mixture was stirred at 150° C. for 4 h under microwave(2 bar). TLC (PE/EtOAc=10/1, R_(f)=0.79) indicated the starting materialwas consumed completely and two new spots formed. The reaction mixturefrom another batch was combined with this batch and worked up together.The combined reaction mixture was quenched by addition of water (100mL), NH₃.H₂O (10 mL) and extracted with EtOAc (60 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (from PE/EtOAc=1/0to 10/1, TLC: PE/EtOAc=10/1, R_(f)=0.79) to yield4-(1,1,2,2,2-pentafluoroethyl)benzonitrile (850 mg, 3.65 mmol, 41.8%yield, 95.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm7.87-7.80 (m, 2H), 7.79-7.72 (m, 2H); ES-LCMS no desired m z was found.

Step 2: 4-(1,1,2,2,2-Pentafluoroethyl)benzaldehyde

To a solution of 4-(1,1,2,2,2-pentafluoroethyl)benzonitrile (400 mg,1.72 mmol, 95%, 1 eq) in THF (10 mL) was added DIBAL-H (1 M, 10.31 mL, 6eq) at −70° C. under N₂ atmosphere. After being stirred for 30 min, themixture was stirred at 20° C. for 1.5 h. TLC (PE/EtOAc=10/1, R_(f)=0.62)indicated half of the starting material was remained and one new spotformed. The reaction mixture was quenched by addition of NH₄Cl (20 mL)and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yield a residue which was purified bypreparative TLC (PE/EtOAc=10/0, TLC: PE/EtOAc=10/1, R_(f)=0.62) to yield4-(1,1,2,2,2-pentafluoroethyl)benzaldehyde (200 mg, 446.18 μmol, 25.9%yield, 50.0% purity) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.13(s, 1H), 8.04 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.2 Hz, 2H); ES-LCMS nodesired m z was found.

Step 3:(5R)-3-Bromo-5-[1-[[4-(1,1,2,2,2-pentafluoroethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 4-(1,1,2,2,2-pentafluoroethyl)benzaldehyde (180 mg,401.56 μmol, 50% purity, 1 eq) in MeOH (8 mL) was added(5R)-3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (219.51 mg, 518.54μmol, 82% purity, 1.29 eq, TFA) and Et₃N (40.63 mg, 401.56 μmol, 55.89μL, 1 eq) at 60° C. for 2 h under N₂ atmosphere. NaBH₃CN (126.17 mg,2.01 mmol, 5 eq) was added. The mixture was stirred at 25° C. for 1 h.The mixture was neutralized with 2 N NaOH to pH 8. The mixture wasconcentrated, diluted with water (80 mL) and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to yield a residue which waspurified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5um; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %:70%-100%, 10 min) to yield(5R)-3-bromo-5-[1-[[4-(1,1,2,2,2-pentafluoroethyl)phenyl]methyl]-4-piperidyl]-4,5-dihydroisoxazole(22.35 mg, 49.64 μmol, 12.4% yield, 98.0% purity, [α]^(23.4) _(D)=−14.7(MeOH, c=0.03 g/100 mL)) as white oil. ¹H NMR (400 MHz, CDCl₃) δ ppm7.55 (d, J=7.8 Hz, 2H), 7.46 (d, J=6.8 Hz, 2H), 4.56-4.43 (m, 1H), 3.55(s, 2H), 3.20 (dd, J=10.6, 17.2 Hz, 1H), 2.96 (dd, J=8.9, 17.2 Hz, 3H),1.99 (s, 2H), 1.85 (d, J=13.0 Hz, 1H), 1.69 (s, 1H), 1.46-1.22 (m, 2H),0.92-0.78 (m, 1H); ES-LCMS m/z 441.1, 443.1 [M+H]⁺.

I-306 & I-307

Step 1: N-(5-Bromo-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-amine

To a solution of 4-bromo-2-iodo-1-methyl-benzene (1 g, 3.37 mmol, 1.3eq) 5-(trifluoromethyl)pyridin-2-amine (419.97 mg, 2.59 mmol, 1 eq) andCs₂CO₃ (1.69 g, 5.18 mmol, 2 eq) in toluene (25 mL) was added Ruphos(181.33 mg, 388.59 μmol, 0.15 eq) and Pd₂(dba)₃ (118.61 mg, 129.53 μmol,0.05 eq) under N₂ atmosphere. The mixture was stirred at 80° C. for 3 h.The reaction mixture was quenched by addition of water (30 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (40 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from pure PE to PE/EtOAc=1/3, TLC: PE/EtOAc=3/1,R_(f)=0.60) to yieldN-(5-bromo-2-methyl-phenyl)-5-(trifluoromethyl)pyridin-2-amine (330 mg,627.85 μmol, 24.2% yield, 63.0% purity) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.45 (br s, 1H), 7.64-7.63 (m, 2H), 7.44-7.43 (m, 2H),7.16-7.15 (m, 1H), 2.23 (s, 3H).

Step 2: N-(2-Methyl-5-vinylphenyl)-5-(trifluoromethyl)pyridin-2-amine

To a solution ofN-(5-bromo-2-methyl-phenyl)-5-(trifluoromethyl)pyridin-2-amine (300 mg,570.77 μmol, 63.0% purity, 1 eq) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (105.49 mg, 684.93 μmol,116.18 μl, 1.2 eq) in 1,4-dioxane (5 mL) and H₂O (1 mL) was added K₂CO₃(118.33 mg, 856.16 μmol, 1.5 eq) and Pd(dppf)Cl₂ (20.88 mg, 28.54 μmol,0.05 eq) under N₂ atmosphere. The mixture was stirred at 90° C. for 2 h.The reaction mixture was quenched by addition of water (8 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by flash silicagel chromatography (from pure PE to PE/EtOAc=3/1, TLC: PE/EtOAc=3/1,R_(f)=0.65) to yieldN-(2-methyl-5-vinyl-phenyl)-5-(trifluoromethyl)pyridin-2-amine (110 mg,351.81 μmol, 61.6% yield, 89.0% purity) as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ ppm 8.41 (s, 1H), 7.65-7.56 (m, 2H), 7.42-7.38 (m, 2H),6.56 (d, J=8.4 Hz, 2H), 5.70 (d, J=17.6 Hz, 1H), 5.23 (d, J=11.2 Hz,1H), 2.28 (s, 3H); ES-LCMS m/z 279.2 [M+H]⁺.

Step 3:(R)—N-(5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-amineand(S)—N-(5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-methylphenyl)-5-(trifluoromethyl)pyridin-2-amine

To a solution ofN-(2-methyl-5-vinyl-phenyl)-5-(trifluoromethyl)pyridin-2-amine (200 mg,574.98 μmol, 80% purity, 1 eq) in EtOAc (5 mL) was added NaHCO₃ (483.02mg, 5.75 mmol, 10 eq) and dibromomethanone oxime (233.25 mg, 1.15 mmol,2 eq) under N₂ atmosphere. The mixture was stirred at 30° C. for 12 h.The reaction mixture was quenched by addition of water (10 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was purified by preparativeHPLC (column: YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water(0.225% FA)-ACN]; B %: 54%-81%, 11 min) to yield desired product whichwas separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um);mobile phase: [0.1% NH₃.H₂O EtOH]; B %: 35%-35%) to yield peak 1 andpeak 2. Peak 1 was concentrated under reduced pressure to yield aresidue which was dissolved in MeCN (2 mL) and water (15 mL) andlyophilized to yieldN-[5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-phenyl]-5-(trifluoromethyl)pyridin-2-amine(21.74 mg, 51.88 μmol, 9.0% yield, 95.5% purity, SFC: R_(t)=4.631,ee=100%, [α]^(26.9) _(D)=+156.571 (DMSO, c=0.175 g/100 mL)) as a whitesolid. H NMR (400 MHz, CDCl₃) δ ppm 8.44 (s, 1H), 7.66 (dd, J=2.0, 8.8Hz, 1H), 7.45 (s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.13 (dd, J=1.2, 7.6 Hz,1H), 6.60 (d, J=8.8 Hz, 1H), 6.55 (s, 1H), 5.70-5.62 (m, 1H), 3.63 (m,1H), 3.22 (m, 1H), 2.29 (s, 3H); ES-LCMS m/z 402.1 [M+H]⁺. Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (2 mL) and water (15 mL) and lyophilized to yieldN-[5-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-methyl-phenyl]-5-(trifluoromethyl)pyridin-2-amine(23.08 mg, 57.67 μmol, 10.0% yield, 100.0% purity, SFC: R_(t)=6.469,ee=100%, [α]^(26.9) _(D)=−3.429 (DMSO, c=0.175 g/100 mL)) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.44 (s, 1H), 7.66 (d, J=8.8 Hz,1H), 7.45 (d, J=1.2 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.13 (dd, J=1.6,8.0 Hz, 1H), 6.63-6.55 (m, 2H), 5.68-5.63 (m, 1H), 3.66-3.59 (m, 1H),3.25-3.19 (m, 1H), 2.29 (s, 3H); ES-LCMS m/z 402.1 [M+H]⁺.

I-308 & I-309

Step 1: 4-(5-Bromo-2-methyl-phenoxy)benzaldehyde

A mixture of 5-bromo-2-methyl-phenol (1 g, 5.35 mmol, 1 eq),4-fluorobenzaldehyde (1 g, 8.06 mmol, 1.51 eq) and K₂CO₃ (1.48 g, 10.69mmol, 2 eq) in DMF (4 mL) was stirred at 120° C. for 12 h. TLC(PE/EtOAc=10/1, R_(f)=0.40) showed the starting material was consumedcompletely. The reaction mixture was diluted with H₂O (50 mL) andextracted with EtOAc (50 mL×3). The organic layer was washed with brine(50 mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=10/1,R_(f)=0.40) to yield 4-(5-bromo-2-methyl-phenoxy)benzaldehyde (1.5 g,4.81 mmol, 90.0% yield, 93.4% purity) as colorless oil. ¹H NMR (500 MHz,CDCl₃) δ ppm 9.94 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.30 (dd, J=1.8, 8.1Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.16 (d, J=1.7 Hz, 1H), 6.99 (d, J=8.7Hz, 2H), 2.16 (s, 3H); ES-LCMS m/z 291.1, 293.1 [M+H]⁺.

Step 2: 4-(2-Methyl-5-vinyl-phenoxy)benzaldehyde

A mixture of 4-(5-bromo-2-methyl-phenoxy)benzaldehyde (1 g, 3.21 mmol,93.4% purity, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1g, 6.49 mmol, 1.10 mL, 2.02 eq), Pd(dppf)Cl₂ (140 mg, 191.33 μmol,5.96e-2 eq) and Cs₂CO₃ (3.14 g, 9.62 mmol, 3 eq) in 1,4-dioxane (20 mL)and H₂O (10 mL) was stirred under N₂ atmosphere at 90° C. for 2 h. TLC(PE/EtOAc=10/1, R_(f)=0.43) showed the starting material was almostconsumed. The reaction mixture was diluted with H₂O (50 mL) andextracted with EtOAc (50 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield a residuewhich was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 20/1, TLC: PE/EtOAc=10/1, R_(f)=0.43) to yield4-(2-methyl-5-vinyl-phenoxy)benzaldehyde (800 mg, 2.52 mmol, 78.5%yield, 75.0% purity) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm9.92 (s, 1H), 7.86-7.83 (m, 2H), 7.25-7.15 (m, 2H), 7.08 (s, 1H), 6.98(d, J=8.6 Hz, 2H), 6.66 (dd, J=10.8, 17.6 Hz, 1H), 5.70 (d, J=17.6 Hz,1H), 5.25 (d, J=10.8 Hz, 1H), 2.17 (s, 3H); ES-LCMS m/z 239.2 [M+H]⁺.

Step 3: 2-(4-Ethynylphenoxy)-1-methyl-4-vinyl-benzene

A mixture of 4-(2-methyl-5-vinyl-phenoxy)benzaldehyde (300 mg, 944.26μmol, 75% purity, 1 eq), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (360mg, 1.87 mmol, 1.98 eq) and K₂CO₃ (360 mg, 2.60 mmol, 2.76 eq) in MeOH(4 mL) was stirred at 15° C. for 12 h. TLC (PE, R_(f)=0.40) showed thestarting material was consumed completely. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (PE, TLC: PE, R_(f)=0.40) to yield2-(4-ethynylphenoxy)-1-methyl-4-vinyl-benzene (150 mg, 608.22 μmol,64.4% yield, 95.0% purity) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δppm 7.44 (d, J=8.7 Hz, 2H), 7.25-7.20 (m, 1H), 7.20-7.14 (m, 1H), 7.01(s, 1H), 6.87-6.81 (m, 2H), 6.64 (dd, J=10.9, 17.6 Hz, 1H), 5.67 (d,J=17.5 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H), 3.03 (s, 1H), 2.19 (s, 3H).

Step 4:(5S)-3-Bromo-5-[3-(4-ethynylphenoxy)-4-methyl-phenyl]-4,5-dihydroisoxazoleand(5R)-3-bromo-5-[3-(4-ethynylphenoxy)-4-methyl-phenyl]-4,5-dihydroisoxazole

A mixture of 2-(4-ethynylphenoxy)-1-methyl-4-vinyl-benzene (150 mg,608.22 μmol, 95% purity, 1 eq), dibromomethanone oxime (150 mg, 739.53μmol, 1.22 eq) and NaHCO₃ (500 mg, 5.95 mmol, 9.79 eq) in EtOAc (4 mL)was stirred at 15° C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.45) showedthe starting material was consumed completely. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (20 mL×3). The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=100/1 to 10/1, TLC: PE/EtOAc=3/1,R_(f)=0.45). The desired fraction was concentrated under reducedpressure to yield a residue which was separated by chiral SFC (column:DAICEL CHIRALCEL OJ-H (250 mm*30 mm, Sum); mobile phase: [0.1%NH₃H₂O/EtOH]; B %: 35%-35%) to yield peak 1 and peak 2. Peak 1 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (10 mL) and water (10 mL) and lyophilized to yield(5S)-3-bromo-5-[3-(4-ethynylphenoxy)-4-methyl-phenyl]-4,5-dihydroisoxazole(42.34 mg, 118.86 μmol, 19.5% yield, 100.0% purity, SFC: R_(t)=4.321,ee=99.90%, [α]^(22.3) _(D)=−147.27 (MeOH, c=0.110 g/100 mL)) as acolorless gum. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.44 (d, J=8.9 Hz, 2H),7.30 (d, J=8.1 Hz, 1H), 7.10 (dd, J=1.8, 7.9 Hz, 1H), 6.93 (d, J=1.7 Hz,1H), 6.82 (d, J=8.9 Hz, 2H), 5.61 (dd, J=9.2, 10.8 Hz, 1H), 3.58 (dd,J=10.8, 17.2 Hz, 1H), 3.18 (dd, J=9.2, 17.2 Hz, 1H), 3.03 (s, 1H), 2.21(s, 3H); ES-LCMS m/z 356.1, 358.1 [M+H]⁺. Peak 2 was concentrated underreduced pressure to yield a residue which was dissolved in MeCN (10 mL)and water (10 mL) and lyophilized to yield(5R)-3-bromo-5-[3-(4-ethynylphenoxy)-4-methyl-phenyl]-4,5-dihydroisoxazole(47.98 mg, 133.14 μmol, 21.9% yield, 98.8% purity, SFC: R_(t)=4.811,ee=98.48%, [α]^(22.1) _(D)=+144.00 (MeOH, c=0.100 g/100 mL)) as acolorless gum. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.44 (d, J=8.9 Hz, 2H),7.32-7.28 (m, 1H), 7.10 (dd, J=1.8, 7.9 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H),6.82 (d, J=8.9 Hz, 2H), 5.61 (dd, J=9.2, 10.7 Hz, 1H), 3.58 (dd, J=10.8,17.2 Hz, 1H), 3.18 (dd, J=9.0, 17.2 Hz, 1H), 3.03 (s, 1H), 2.21 (s, 3H);ES-LCMS m/z 356.1, 358.1 [M+H]⁺.

I-237

Step 1: (4-Cyclopropylphenyl)methyl methanesulfonate

To a solution of (4-cyclopropylphenyl)methanol (300 mg, 2.02 mmol, 1 eq)in DCM (5 mL) was added Et₃N (614.51 mg, 6.07 mmol, 845.27 μL, 3 eq) andMsCl (278.26 mg, 2.43 mmol, 188.01 μL, 1.2 eq) at 0° C. The mixture wasstirred at 25° C. for 2 h. TLC (PE/EtOAc=3/1, R_(f)=0.47) indicated thestarting material was consumed completely and one new spots formed. Tothe ice water was added the reaction mixture slowly and the mixture wasadjusted pH to 7-8 by sat. aq. NaHCO₃. The mixture was extracted withEtOAc (30 mL×3). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum to yield(4-cyclopropylphenyl) methyl methanesulfonate (300 mg, 1.06 mmol, 52.4%yield, 80.0% purity) as yellow oil, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.35 (d,J=7.8 Hz, 1H), 7.29 (s, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.2 Hz,1H), 3.37 (q, J=7.3 Hz, 3H), 3.18-3.05 (m, 2H), 1.91 (d, J=7.8 Hz, 1H),1.09-1.01 (m, 1H), 0.98 (dd, J=1.8, 8.4 Hz, 1H), 0.76-0.68 (m, 2H).

Step 2:(S)3-Bromo-5-[1-[(4-cyclopropylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole

To a solution of 3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (400 mg,1.04 mmol, 1 eq, TFA) in THE (8 mL) was added Et₃N (629.65 mg, 6.22mmol, 866.09 μL, 6.00 eq) and (4-cyclopropylphenyl)methylmethanesulfonate (293.35 mg, 1.04 mmol, 1 eq). The mixture was stirredunder N₂ atmosphere at 28° C. for 4 h. TLC (PE/EtOAc=3/1, R_(f)=0.40)indicated the starting material was consumed completely and one newspots formed. The mixture was diluted with water (30 mL) and extractedwith EtOAc (30 mL×3). The combined organic phase was washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuum to yield a residue which was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.05%NH₃.H₂O+10 mM NH₄HCO₃)-ACN]; B %: 55%-85%, 10 min), followed bylyophilization to yield product. The product was separated by SFC(column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1%NH₃.H₂O EtOH]; B %: 25%-25%) to yield peak 1 (R_(t)=1.333 min,ee=99.06%) and peak 2 (R_(t)=1.417 min, ee=94.90%). Peak 2 wasconcentrated under reduced pressure to yield a residue which wasdissolved in MeCN (20 mL) and H₂O (40 mL) and lyophilized to yield(S)3-bromo-5-[1-[(4-cyclopropylphenyl)methyl]-4-piperidyl]-4,5-dihydroisoxazole(38.52 mg, 106.03 μmol, 10.2% yield, 100.0% purity, R_(t)=1.417,ee=94.90%, [α]^(23D)=−87.500 (c=0.032 g/100 mL)) as a white solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.21 (d, J=7.8 Hz, 2H), 7.03 (d, J=7.9 Hz,2H), 4.53-4.43 (m, 1H), 3.52 (s, 2H), 3.17 (dd, J=10.6, 17.2 Hz, 1H),3.03-2.91 (m, 3H), 2.08-1.92 (m, 2H), 1.91-1.87 (m, 1H), 1.84 (d, J=13.0Hz, 1H), 1.62 (dd, J=3.8, 7.0 Hz, 1H), 1.54 (s, 1H), 1.47-1.38 (m, 2H),0.99-0.91 (m, 2H), 0.71-0.67 (m, 2H); ES-LCMS m/z 363.2, 365.2 [M+H]⁺.

I-242

Step 1: tert-Butyl6-prop-2-enoyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine-1-carboxylate (1 g,4.42 mmol, 1 eq) in DCM (10 mL) was added DIEA (1.71 g, 13.26 mmol, 2.31mL, 3 eq) and prop-2-enoyl chloride (599.88 mg, 6.63 mmol, 540.44 μL,1.5 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. TLC(PE/EtOAc=3/1, R_(f)=0.45) indicated the starting material was consumedcompletely and one new spots formed. The mixture was quenched with water(30 mL) and extracted with DCM (30 mL×3). The combined organic phase waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 3/1, TLC:PE/EtOAc=3/1, R_(f)=0.45) to yield tert-butyl6-prop-2-enoyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.1 g, 3.81 mmol, 86.1% yield, 97.0% purity) as yellow oil. H NMR (500MHz, CDCl₃) δ ppm 6.68 (dd, J=10.5, 16.6 Hz, 1H), 6.34-6.30 (m, 1H),5.69 (d, J=10.4 Hz, 1H), 3.98 (dd, J=5.3, 14.2 Hz, 1H), 3.76 (s, 2H),3.38 (d, J=5.2 Hz, 2H), 3.15-3.06 (m, 1H), 2.50-2.38 (m, 2H), 1.90 (d,J=4.9 Hz, 3H), 1.58 (d, J=5.0 Hz, 1H), 1.46 (s, 9H); ES-LCMS m/z 281.3[M+H]⁺.

Step 2:1-(1,2,3,3a,4,5,7,7a-Octahydropyrrolo[2,3-c]pyridin-6-yl)prop-2-en-1-one

A mixture of tert-butyl6-prop-2-enoyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.1 g, 3.81 mmol, 1 eq) in TFA (4 mL) and DCM (10 mL) was stirred underN₂ atmosphere at 25° C. for 1 h. The reaction mixture was concentratedunder reduced pressure to yield1-(1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridin-6-yl)prop-2-en-1-one(1.1 g, 3.70 mmol, 97.2% yield, 99.0%, TFA) as yellow oil, which wasused in the next step without further purification. ¹H NMR (500 MHz,CDCl₃) δ ppm 6.70-6.45 (m, 1H), 6.20 (d, J=16.6 Hz, 1H), 5.80 (d, J=10.5Hz, 1H), 4.81 (d, J=15.0 Hz, 1H), 3.99 (d, J=13.0 Hz, 1H), 3.88 (s, 1H),3.63-3.41 (m, 2H), 3.32 (d, J=15.7 Hz, 1H), 3.20 (t, J=11.8 Hz, 1H),2.60 (s, 1H), 2.66-2.55 (m, 1H), 2.34-2.22 (m, 1H), 1.93 (d, J=10.1 Hz,2H), 1.73 (d, J=10.4 Hz, 1H); ES-LCMS m/z 181.2 [M+H]⁺.

Step 3:1-[(3aR,7aR)-1-[[4-(Trifluoromethyl)phenyl]methyl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one

To a solution of1-(1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridin-6-yl)prop-2-en-1-one(400 mg, 1.35 mmol, 1 eq, TFA) in DCM (10 mL) was added DIEA (1.04 g,8.07 mmol, 1.41 mL, 6 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene(321.67 mg, 1.35 mmol, 207.53 μL, 1 eq). The mixture was stirred at 25°C. for 1 h. The mixture was diluted with water (30 mL) and extractedwith DCM (30 mL×3). The combined organic phase was washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum toyield a residue which was purified by flash silica gel chromatography(from PE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1, R_(f)=0.35) to yield theproduct. The product was separated by SFC (column: DAICEL CHIRALPAK IG(250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃.H₂O/EtOH]; B %: 20%-20%)to yield peak 1 (R_(t)=2.662 min, ee=99.87%) and peak 2 (R_(t)=2.968min, ee=99.72%). Peak 1 was purified by preparative HPLC (column: AgelaDuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.05% NH₃.H₂O+10 mMNH₄HCO₃)-ACN]; B %: 44%-74%, 10 min), followed by lyophilization toyield1-[(3aR,7aR)-1-[[4-(trifluoromethyl)phenyl]methyl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]prop-2-en-1-one(14.24 mg, 42.08 μmol, 3.1% yield, 100.0% purity, SFC: R_(t)=2.662,ee=99.87%, [α]^(23.1) _(D)=+20.689 (MeOH, c=0.029 g/100 mL)) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.60-7.47 (m, 2H), 7.39 (t,J=7.8 Hz, 2H), 6.61 (dd, J=10.6, 16.8 Hz, 1H), 6.67-6.17 (m, 1H),5.77-5.46 (m, 1H), 4.26-4.18 (m, 1H), 4.06-3.89 (m, 1H), 3.86-3.59 (m,1H), 3.51-3.41 (m, 1H), 3.39-3.28 (m, 1H), 3.25-3.11 (m, 1H), 3.02-2.82(m, 1H), 2.75-2.64 (m, 1H), 2.40-2.28 (m, 1H), 2.26-2.13 (m, 1H),1.98-1.87 (m, 1H), 1.78 (d, J=5.9 Hz, 1H), 1.70-1.64 (m, 1H), 1.56-1.42(m, 1H); ES-LCMS m/z 339.2 [M+H]⁺.

I-386

Step 1: tert-Butyl N-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate

To a solution of tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (2 g,10.74 mmol, 1 eq) in DCM (25 mL) was added DIEA (5.94 g, 45.93 mmol, 8mL, 4.28 eq) and prop-2-enoyl chloride (1.22 g, 13.49 mmol, 1.1 mL, 1.26eq) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. TLC(PE/EtOAc=1/1, R_(f)=0.24) showed the starting material was consumedcompletely. The reaction mixture was diluted with H₂O (50 mL) andextracted with EtOAc (50 mL×3). The combined organic layers dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by flash silica gel chromatography (fromPE/EtOAc=100/1 to 1/1, TLC: PE/EtOAc=1/1, R_(f)=0.24) to yieldtert-butyl N-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate (2 g, 7.49mmol, 69.8% yield, 90.0% purity) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 6.58 (dt, J=10.4, 17.3 Hz, 1H), 6.26 (td, J=2.3, 16.8 Hz,1H), 5.74 (td, J=2.5, 10.3 Hz, 1H), 4.20-4.08 (m, 1H), 3.88-3.54 (m,3H), 3.47-3.33 (m, 1H), 2.24-2.08 (m, 1H), 2.00-1.84 (m, 1H), 1.45 (s,9H); ES-LCMS m/z 241.3 [M+H]⁺.

Step 2: 1-[(3R)-3-Aminopyrrolidin-1-yl]prop-2-en-1-one

To a solution of tert-butylN-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]carbamate (200 mg, 749.07 μmol, 1eq) in DCM (3 mL) was added TFA (2.31 g, 20.26 mmol, 1.5 mL, 27.05 eq).The mixture was stirred at 25° C. for 1 h. TLC (PE/EtOAc=1/1,R_(f)=0.05) showed the starting material was consumed completely. Thereaction mixture was concentrated under reduced pressure to yield1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (105 mg, 413.05 μmol,55.1% yield, N/A purity, TFA) as colorless oil which was used in thenext step without further purification. ¹H NMR (500 MHz, CD₃OD) δ ppm6.67-6.53 (m, 1H), 6.35-6.26 (m, 1H), 5.79 (dd, J=1.7, 10.5 Hz, 1H),4.02-3.69 (m, 4H), 3.68-3.62 (m, 1H), 2.50-2.33 (m, 1H), 2.22-2.04 (m,1H).

Step 3:1-[(3R)-3-[[3-(Trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one

To a solution of 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (105 mg,749.02 μmol, 1 eq) in DCM (3 mL) was added DIEA (742.00 mg, 5.74 mmol, 1mL, 7.66 eq) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (180 mg,753.04 μmol, 114.65 μL, 1.01 eq). The mixture was stirred at 25° C. for12 h. TLC (PE/EtOAc=1/1, R_(f)=0.08) showed the starting material wasconsumed completely. The reaction mixture was diluted with H₂O (20 mL)and extracted with EtOAc (20 mL×3). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield aresidue which was purified by preparative HPLC (column: PhenomenexSynergi C18 150*30 mm*4 um; mobile phase: [water (0.05% HCl)-ACN]; B %:12%-32%, 10 min). The desired compound was basified with saturatedaqueous NaHCO₃ until pH=8 and extracted with EtOAc (50 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue which was dissolved in MeCN (10 mL)and water (10 mL) and lyophilized to yield1-[(3R)-3-[[3-(trifluoromethyl)phenyl]methylamino]pyrrolidin-1-yl]prop-2-en-1-one(17.41 mg, 58.36 μmol, 7.8% yield, 100.0% purity, ([α]^(24.5)_(D)=+34.783 (MeOH, c=0.023 g/100 mL)) as colorless oil. 1H NMR (400MHz, CD₃OD) δ ppm 7.72 (s, 1H), 7.64 (d, J=7.0 Hz, 1H), 7.59-7.55 (m,1H), 7.55-7.50 (m, 1H), 6.58 (ddd, J=10.6, 14.5, 16.8 Hz, 1H), 6.32-6.22(m, 1H), 5.78-5.69 (m, 1H), 3.90-3.87 (m, 2H), 3.86-3.68 (m, 2H),3.68-3.58 (m, 1H), 3.52-3.32 (m, 3H), 2.22-2.10 (m, 1H), 1.97-1.78 (m,1H); ES-LCMS m/z 299.3 [M+H]⁺.

I-246

Step 1: 1-(Bromomethyl)-4-(trifluoromethylsulfonyl)benzene

To a solution of 1-(bromomethyl)-4-(trifluoromethylsulfanyl)benzene (250mg, 922.18 μmol, 1 eq) in DCM (5 mL) was added m-CPBA (1.09 g, 5.35mmol, 85% purity, 5.80 eq). The mixture was stirred at 40° C. for 16 h.The reaction mixture was added sat.aq. NaHCO₃ until to pH 8 and dilutedwith H₂O (20 mL), extracted with EtOAc (30 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield a residue which was purified by flash silica gelchromatography (from PE/EtOAc=1/0 to 9/1, TLC: PE/EtOAc=3/1, R_(f)=0.65)to yield 1-(bromomethyl)-4-(trifluoromethylsulfonyl)benzene (240 mg,791.83 μmol, 85.9% yield, 100.0% purity) as colorless oil. ¹H NMR (400MHz, CDCl₃) δ ppm 8.03 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.6 Hz, 2H), 4.54(s, 2H).

Step 2:N-[1-[[4-(Trifluoromethylsulfonyl)phenyl]methyl]-4-piperidyl]prop-2-enamide

To a solution of 1-(bromomethyl)-4-(trifluoromethylsulfonyl)benzene (100mg, 329.93 μmol, 1 eq) in DCM (15 mL) was addedN-(4-piperidyl)prop-2-enamide (81.78 mg, 428.91 μmol, 1.3 eq, HCl) andEt₃N (100.16 mg, 989.79 μmol, 137.77 μL, 3 eq). The mixture was stirredat 20° C. for 16 h. The reaction mixture was concentrated to yield aresidue which was purified by preparative HPLC (column: Agela DuraShellC18 150*25 mm*5 μm; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 32%-62%, 10 min). The desired fraction waslyophilization to yieldN-[1-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-4-piperidyl]prop-2-enamide(20.59 mg, 54.70 μmol, 16.6% yield, 100.0% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.99 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.6 Hz,2H), 6.30 (dd, J=1.2, 16.9 Hz, 1H), 6.13-6.03 (m, 1H), 5.66 (dd, J=1.5,10.3 Hz, 1H), 5.46-5.25 (m, 1H), 3.99-3.88 (m, 1H), 3.63 (s, 2H), 2.81(d, J=11.7 Hz, 2H), 2.22 (t, J=10.5 Hz, 2H), 1.99 (d, J=12.5 Hz, 2H),1.56-1.46 (m, 2H); ES-LCMS m/z 377.2 [M+H]⁺.

I-248

Step 1: tert-Butyl (3R)-3-formylpyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (8 g, 39.75 mmol, 1 eq)in DCM (100 mL) was added Dess-Martin (20.23 g, 47.70 mmol, 1.2 eq). Themixture was stirred at 20° C. for 4 h. TLC (PE/EtOAc=3/1, R_(f)=0.30)indicated starting material was consumed completely and one new spotformed. The reaction mixture was quenched by addition of water (500 mL),extracted with EtOAc (500 mL×3). The combined organic layers were washedwith brine (400 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue which was purified by flash silicagel chromatography (from PE/EtOAc=1/0 to 3/1, TLC:PE/EtOAc=3/1,R_(f)=0.30) to yield tert-butyl (3R)-3-formylpyrrolidine-1-carboxylate(6 g, 28.61 mmol, 72.0% yield, 95% purity) as a colorless liquid. ¹H NMR(400 MHz, CDCl₃) δ ppm 9.65 (d, J=1.5 Hz, 1H), 3.66 (d, J=9.5 Hz, 1H),3.57-3.43 (m, 1H), 3.41-3.25 (m, 2H), 2.99 (s, 1H), 2.24-2.03 (m, 2H),1.42 (s, 9H)

Step 2: tert-Butyl (3S)-3-vinylpyrrolidine-1-carboxylate

To a solution of methyl(triphenyl)phosphonium; bromide (2.45 g, 6.87mmol, 1.2 eq) in THE (30 mL) was cooled to −65° C., added n-BuLi (2.75mL, 2.5 M, 1.2 eq) dropwise under N₂ atmosphere. The mixture was stirredat 0° C. for 0.5 h under N₂ atmosphere. The mixture was cooled to −65°C. and a solution of tert-butyl (3R)-3-formylpyrrolidine-1-carboxylate(1.2 g, 5.72 mmol, 1 eq) in THF (4 mL) was added slowly. The mixture wasstirred at 20° C. for 12 h under N₂ atmosphere. TLC (PE/EtOAc=10/1,R_(f)=0.59) indicated starting material was consumed completely and onenew spot formed. The reaction mixture was quenched by addition of NH₄Cl(50 mL), extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine (40 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue which was purifiedby flash silica gel chromatography (from PE/EtOAc=1/0 to 10/1, TLC:PE/EtOAc=10/1, R_(f)=0.59) to yield tert-butyl(3S)-3-vinylpyrrolidine-1-carboxylate (1.05 g, 4.79 mmol, 83.7% yield,90% purity) as colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.84-5.66(m, 1H), 5.08 (d, J=17.1 Hz, 1H), 5.01 (d, J=10.4 Hz, 1H), 3.58-3.37 (m,2H), 3.32-3.20 (m, 1H), 3.09-2.96 (m, 1H), 2.79-2.70 (m, 1H), 2.02-1.94(m, 1H), 1.71-1.63 (m, 1H), 1.44 (s, 9H).

Step 3: tert-Butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate

To a solution of tert-butyl (3S)-3-vinylpyrrolidine-1-carboxylate (1.05,4.79 mmol, 1 eq) in EtOAc (20 mL) was added NaHCO₃ (4.02 g, 47.90 mmol,10 eq) and dibromomethanone oxime (1.17 g, 5.75 mmol, 1.2 eq). Themixture was stirred at 20° C. for 12 h. TLC (PE/EtOAc=3/1, R_(f)=0.34)indicated starting material was consumed completely and one new spotformed. The reaction mixture was quenched by addition of water (50 mL),extracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine (40 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield tert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (1.2g, 3.38 mmol, 70.6% yield, 90% purity) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.75-4.48 (m, 1H), 3.40-3.25 (m, 3H), 3.18-3.03 (m, 2H),2.99-2.81 (m, 1H), 2.45-2.27 (m, 1H), 1.94-1.82 (m, 1H), 1.68-1.45 (m,1H), 1.35 (s, 9H).

Step 4: 3-Bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole

To a solution of tert-butyl(3R)-3-(3-bromo-4,5-dihydroisoxazol-5-yl)pyrrolidine-1-carboxylate (300mg, 845.88 μmol, 1 eq) in DCM (5 mL) was added TFA (1.35 mL, 18.23 mmol)and the mixture was stirred at 25° C. for 2 h. TLC (PE/EtOAc=3/1,R_(f)=0) indicated starting material was consumed completely and one newspot formed. The reaction mixture was concentrated under reducedpressure to yield 3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole(300 mg, 810.56 μmol, 95.8% yield, 90% purity, TFA) as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 4.82-4.41 (m, 1H), 3.47-2.82 (m, 6H),2.59-2.39 (m, 1H), 2.15-1.94 (m, 1H), 1.87-1.45 (m, 1H), 1.41-1.31 (m,1H).

Step 5:(5R)-5-[(3R)-1-Benzylpyrrolidin-3-yl]-3-bromo-4,5-dihydroisoxazole

To a solution of 3-bromo-5-[(3R)-pyrrolidin-3-yl]-4,5-dihydroisoxazole(300 mg, 810.56 μmol, 1 eq, TFA) in DMF (3 mL) was added DIEA (523.79mg, 4.05 mmol, 705.91 μL, 5 eq) and bromomethylbenzene (207.95 mg, 1.22mmol, 144.41 μL, 1.5 eq). The mixture was stirred at 20° C. for 12 h.The reaction mixture was quenched by addition of water (40 mL),extracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield a residue, which was purified by preparativeHPLC (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase:[water (0.05% HCl)-ACN]; B %: 11%-31%, 9 min]; B %: 60%-90%, 10 min) toyield a residue which was separated by SFC (column: DAICEL CHIRALPAK IG(250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 50%-50%,min) to yield(5R)-5-[(3R)-1-benzylpyrrolidin-3-yl]-3-bromo-4,5-dihydroisoxazole(55.80 mg, 179.02 μmol, 22.1% yield, 99.2% purity, SFC: R_(t)=3.958 min,ee=99.4%; [α]^(29.0) _(D)=−78.0, MeOH, c=0.123 g/100 mL) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ ppm 7.35-7.27 (m, 4H), 7.26-7.23 (m, 1H), 4.66(t, J=6.7, 9.6 Hz, 1H), 3.64-3.54 (m, 2H), 3.24-3.15 (m, 1H), 3.13-3.02(m, 1H), 2.65 (t, J=5.3, 8.7 Hz, 1H), 2.60-2.47 (m, 3H), 2.41-2.31 (m,1H), 2.12-1.92 (m, 1H), 1.74-1.54 (m, 1H); ES-LCMS m/z 308.8, 310.8[M+H]⁺.

I-269

Step 1: tert-Butyl4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-vinylpiperidine-1-carboxylate(14.5 g, 65.19 mmol, 1 eq) in EtOAc (200 mL) was added NaHCO₃ (54.77 g,651.92 mmol, 10 eq) and dibromomethanone oxime (15.87 g, 78.23 mmol, 1.2eq). The reaction mixture was stirred at 20° C. for 12 h. TLC(PE/EtOAc=3/1, R_(f)=0.25) showed starting material was consumedcompletely and one new spot was detected. The reaction mixture wasdiluted with water (200 mL) then extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated to yield a residue which was purified by flashsilica gel chromatography (from PE/EtOAc=100/1 to 3/1, TLC:PE/EtOAc=3/1, R_(f)=0.25) to yield tert-butyl4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (14 g,39.91 mmol, 61.2% yield, 95% purity) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 4.54-4.41 (m, 1H), 4.26-4.10 (m, 2H), 3.20 (dd, J=10.8,17.1 Hz, 1H), 2.94 (dd, J=8.8, 17.1 Hz, 1H), 2.67 (s, 2H), 1.82 (d,J=13.2 Hz, 1H), 1.78-1.67 (m, 1H), 1.55 (d, J=13.0 Hz, 1H), 1.45 (s,9H), 1.25-1.14 (m, 2H).

Step 2: (5R)-3-Bromo-5-(4-piperidyl)-4,5-dihydroisoxazole

To a stirred solution of tert-butyl4-(3-bromo-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate (14 g,39.91 mmol, 1 eq) in DCM (90 mL) was added TFA (46.20 g, 405.19 mmol, 30mL, 10.15 eq). The reaction mixture was stirred at 25° C. for 2 h. TLC(PE/EtOAc=3/1, R_(f)=0.25) showed starting material was consumedcompletely and one new spot was detected. The reaction mixture wasconcentrated to yield a residue which was dissolved in DCM (100 mL),adjusted pH to 8-9 by Na₂CO₃ solid then filtered. The filtrate wasconcentrated to yield a residue which was separated by SFC (column:DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂OEtOH]; B %: 30%-30%, min) to yield peak 1 (R_(t)=4.075 min) and peak 2(R_(t)=4.401 min). Peak 2 was concentrated under reduced pressure toyield a residue which was lyophilized to yield(5R)-3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (2.5 g, 9.89 mmol,24.8% yield, 92.2% purity, SFC: R_(t)=4.401 min, ee=94.50%) as yellowoil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.50-4.34 (m, 1H), 3.32 (d, J=10.8Hz, 1H), 3.05 (dd, J=8.8, 17.6 Hz, 1H), 2.91 (d, J=11.5 Hz, 2H), 2.38(q, J=10.0 Hz, 2H), 1.65-1.50 (m, 2H), 1.41 (d, J=12.2 Hz, 1H),1.13-0.96 (m, 2H); ES-LCMS m/z 233.1, 235.1 [M+H]⁺.

Step 3:(5R)-3-Bromo-5-[1-(p-tolylmethyl)-4-piperidyl]-4,5-dihydroisoxazole

To a stirred solution of(5R)-3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole (70 mg, 276.87 μmol, 1eq) in DMF (2 mL) was added DIEA (71.57 mg, 553.74 μmol, 96.45 μL, 2 eq)and 1-(bromomethyl)-4-methyl-benzene (53.80 mg, 290.71 μmol, 1.05 eq).The reaction mixture was stirred at 15° C. for 12 h. The reactionmixture was filtered and the filtrate was purified by preparative HPLC(column: Agela DuraShell C18 150*25 mm*5 um; mobile phase: [water (0.04%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 50%-80%, 10 min). The desired fractionwas lyophilized to yield(5R)-3-bromo-5-[1-(p-tolylmethyl)-4-piperidyl]-4,5-dihydroisoxazole(27.91 mg, 82.76 μmol, 29.9% yield, 100% purity, [α]^(18.2) _(D)=−164.0(MeOH, c=0.10 g/100 mL)) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.22-7.04 (m, 4H), 4.51-4.37 (m, 1H), 3.37 (s, 2H), 3.28 (d, J=10.5 Hz,1H), 3.07 (dd, J=8.8, 17.6 Hz, 1H), 2.79 (d, J=11.2 Hz, 2H), 2.27 (s,3H), 1.92-1.76 (m, 2H), 1.66 (d, J=12.7 Hz, 1H), 1.51-1.43 (m, 2H),1.25-1.12 (m, 2H); ES-LCMS m/z 337.2, 339.2 [M+H]⁺.

I-297

Step 1: Methyl 2-hydroxy-2-[4-(trifluoromethyl)phenyl]acetate

To a solution of 2-hydroxy-2-[4-(trifluoromethyl)phenyl]acetic acid (4.5g, 20.44 mmol, 1 eq) in MeOH (30 mL) was added DMF (747.02 mg, 10.22mmol, 786.34 μL, 0.5 eq) and SOCl₂ (4.86 g, 40.88 mmol, 2.97 mL, 2 eq).The mixture was stirred at 70° C. for 12 h under N₂. TLC (PE/EtOAc=3/1,R_(f)=0.41) indicated starting material was consumed completely and twonew spots formed. The mixture was concentrated and then sat. aq NaHCO₃(80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to yield a residue which was purifiedby flash silica gel chromatography (From PE/EtOAc=1/0 to 3/1,R_(f)=0.41) to yield methyl2-hydroxy-2-[4-(trifluoromethyl)phenyl]acetate (4.7 g, 16.06 mmol, 78.6%yield, 80.0% purity) as white liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm7.65-7.62 (m, 2H), 7.58-7.56 (m, 2H), 5.25 (d, J=5.1 Hz, 1H), 3.78 (s,3H), 3.55 (d, J=5.5 Hz, 1H).

Step 2: Methyl 2-bromo-2-[4-(trifluoromethyl)phenyl]acetate

To a solution of methyl 2-hydroxy-2-[4-(trifluoromethyl)phenyl]acetate(4.7 g, 16.06 mmol, 80% purity, 1 eq) in DCM (30 mL) was added PPh₃(4.21 g, 16.06 mmol, 1 eq) at 0° C., then added CBr₄ (5.32 g, 16.06mmol, 1 eq). The mixture was stirred at 25° C. for 12 h under N₂. TLC(PE/EtOAc=5/1, R_(f)=0.72) indicated starting material was consumedcompletely and two new spots formed. The mixture was concentrated andthen water (80 mL) was added. The mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to yield a residue which waspurified by flash silica gel chromatography (From PE/EtOAc=1/0 to 5/1,R_(f)=0.72) to yield methyl 2-bromo-2-[4-(trifluoromethyl)phenyl]acetate(4.3 g, 11.58 mmol, 72.1% yield, 80.0% purity) as light yellow liquid.¹H NMR (400 MHz, CDCl₃) δ ppm 7.69-7.66 (m, 2H), 7.64-7.62 (m, 2H), 5.37(s, 1H), 3.81 (s, 3H).

Step 3: Methyl(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetate& Methyl(2R)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetate

To a stirred solution of 3-bromo-5-(4-piperidyl)-4,5-dihydroisoxazole(2.5 g, 6.48 mmol, 90% purity, 1 eq, TFA) in DMF (30 mL) was added DIEA(4.19 g, 32.41 mmol, 5.65 mL, 5 eq) and methyl2-bromo-2-[4-(trifluoromethyl)phenyl]acetate (2.53 g, 6.81 mmol, 80%purity, 1.05 eq). The reaction mixture was stirred at 15° C. for 12 h.The reaction mixture was diluted with water (100 mL) then extracted withEtOAc (50 mL×4). The combined organic layers were dried over Na₂SO₄,filtered and the filtrate was concentrated to yield a residue which waspurified by flash silica gel chromatography (from PE/EtOAc=100/1 to 3/1,TLC: PE/EtOAc=3/1, R_(f)=0.50) then separated by SFC (column: DAICELCHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 20%-20%, min) to yield peak 1 (R_(t)=2.651 min) and peak 2(R_(t)=2.911 min). Peak 1 was concentrated under reduced pressure toyield a residue which lyophilized to yield methyl(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetate(250 mg, 556.47 μmol, 8.6% yield, 100% purity, SFC: R_(t)=2.651 min,ee=97.5%, [α]^(20.8) _(D)=−113.511 (MeOH, c=0.125 g/100 mL)) as yellowoil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.74 (d, J=8.1 Hz, 2H), 7.61 (d,J=8.2 Hz, 2H), 4.50-4.41 (m, 1H), 4.32 (s, 1H), 3.72-3.53 (m, 3H),3.29-3.25 (m, 1H), 3.07 (dd, J=8.7, 17.5 Hz, 1H), 2.82 (d, J=11.0 Hz,1H), 2.69 (d, J=10.2 Hz, 1H), 2.14-2.05 (m, 1H), 1.97-1.88 (m, 1H), 1.64(d, J=12.8 Hz, 1H), 1.56-1.44 (m, 2H), 1.31-1.14 (m, 2H); ES-LCMS m/z449.0, 451.0 [M+H]⁺. Peak 2 was concentrated under reduced pressure toyield a residue which was lyophilized to yield Methyl(2R)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetate(250 mg, 556.47 μmol, 8.6% yield, 100% purity, SFC: R_(t)=2.911 min,ee=98.3%, [α]^(20.8) _(D)=−50.377 (MeOH, c=0.175 g/100 mL)) as yellowoil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.73 (d, J=8.1 Hz, 2H), 7.61 (d,J=8.1 Hz, 2H), 4.52-4.38 (m, 1H), 4.32 (s, 1H), 3.68-3.58 (m, 3H),3.30-3.26 (m, 1H), 3.06 (dd, J=8.7, 17.5 Hz, 1H), 2.82 (d, J=11.1 Hz,1H), 2.69 (d, J=11.3 Hz, 1H), 2.14-2.03 (m, 1H), 1.99-1.90 (m, 1H), 1.69(d, J=12.8 Hz, 1H), 1.56-1.40 (m, 2H), 1.29-1.16 (m, 2H); ES-LCMS m/z449.1, 451.1 [M+H]⁺.

Step 4:(2S)-2-[4-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid

To a stirred solution of methyl(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetate(140.00 mg, 311.62 μmol, 100% purity, 1 eq) in i-PrOH (1.5 mL)/THF (1.5mL)/water (1.5 mL) was added LiOH (22.39 mg, 934.87 μmol, 3 eq). Thereaction mixture was stirred at 70° C. for 1 h. The reaction mixture wasconcentrated to yield(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid (150 mg, crude) as yellow solid which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.63-7.47(m, 4H), 4.50-4.36 (m, 1H), 3.49 (d, J=4.6 Hz, 1H), 3.32-3.18 (m, 3H),3.11-2.99 (m, 1H), 1.87 (t, J=11.7 Hz, 1H), 1.73-1.52 (m, 2H), 1.50-1.32(m, 2H), 1.30-1.22 (m, 1H), 1.18-1.09 (m, 1H); ES-LCMS m/z 435.0, 437.0[M+H]⁺.

Step 5:(2S)-2-[4-[(5R)-3-Bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetamide

To a stirred solution of(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]aceticacid (40 mg, 91.90 μmol, 1 eq) in DMF (3 mL) was added NH₄Cl (14.75 mg,275.71 μmol, 3 eq), HATU (69.89 mg, 183.81 μmol, 2 eq) and DIEA (59.39mg, 459.52 μmol, 80.04 μL, 5 eq). The reaction mixture was stirred at50° C. for 2 h. The reaction mixture was filtered and the filtrate waspurified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 33%-53%, 15 min). Thedesired fraction was lyophilized to yield(2S)-2-[4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-1-piperidyl]-2-[4-(trifluoromethyl)phenyl]acetamide(9.04 mg, 20.82 μmol, 22.65% yield, 100% purity, [α]^(21.2) _(D)=−86.0(MeOH, c=0.100 g/100 mL)) as white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm7.69-7.60 (m, 4H), 4.50 (dt, J=6.5, 9.6 Hz, 1H), 3.91 (s, 1H), 3.30-3.23(m, 1H), 3.14 (d, J=11.0 Hz, 1H), 3.10-2.99 (m, 1H), 2.69 (d, J=11.5 Hz,1H), 2.19-2.06 (m, 1H), 1.87-1.68 (m, 2H), 1.66-1.46 (m, 3H), 1.45-1.31(m, 1H); ES-LCMS m/z 434.0, 436.0 [M+H]⁺.

Example 2. TEAD Inhibition Assay

TEAD inhibition can be assayed using Hippo Pathway TEAD Reporter—MCF7Cell Line (BPS Bioscience, Catalog #: 60618).

Background

The Hippo pathway regulates cell proliferation and cell death. It isactivated by high cell density and cell stress to stop cellproliferation and induce apoptosis. The mammalian Hippo pathwaycomprises MST kinases and LATS kinases. When the Hippo pathway isactivated, MST kinases phosphorylate LATS kinases, which phosphorylatetranscriptional co-activators YAP and TAZ. Unphosphorylated YAP and TAZremain in nucleus and interact with TEAD/TEF transcriptional factors toturn on cell cycle-promoting gene transcription. However, whenphosphorylated, YAP and TAZ are recruited from the nucleus to thecytosol, so that the YAP and TAZ-dependent gene transcription is turnedoff. Dysfunction of the Hippo pathway is frequently detected in humancancer and its down-regulation correlates with the aggressive propertiesof cancer cells and poor prognosis.

Description

The TEAD Reporter—MCF7 cell line contains the firefly luciferase geneunder the control of TEAD responsive elements stably integrated into thehuman breast cancer cell line, MCF7. Inside the cells, basalunphosphorylated YAP/TAZ remains in the nucleus and induces theconstitutive expression of luciferase reporter. The cell line isvalidated for the inhibition of the expression of luciferase reporter bythe activators of the Hippo pathway.

Application

-   -   Monitor Hippo pathway activity.    -   Screen for activators or inhibitors of the Hippo pathway.        Format

Each vial contains ˜1.5×106 cells in 1 ml of 10% DMSO.

Storage

Immediately upon receipt, store in liquid nitrogen.

General Culture Conditions

Thaw Medium 1 (BPS Bioscience #60187)+10 μg/ml of Insulin (Sigma-Aldrich#I0516): MEM medium (Hyclone #SH30024.01) supplemented with 10% FBS(Invitrogen #26140-079), 1% non-essential amino acids (Hyclone#SH30238.01), 1 mM Na pyruvate (Hyclone #SH30239.01), 1%Penicillin/Streptomycin (Hyclone SV30010.01), plus 10 μg/ml of insulin(Sigma-Aldrich #10516)

Growth Medium 1B (BPS Bioscience #79531)+10 μg/ml of Insulin(Sigma-Aldrich #I0516): Thaw Medium 1 (BPS Cat. #60187)+10 μg/ml ofinsulin (Sigma-Aldrich #I0516), and 400 μg/ml of Geneticin (invitrogen#11811031).

Cells should be grown at 37° C. with 5% CO₂ using Growth Medium 1B with10 μg/ml of Insulin. It may be necessary to adjust the percentage of CO₂in the incubator depending on the NaHCO₃ level in the basal medium.

To thaw the cells, it is recommended to quickly thaw the frozen cellsfrom liquid nitrogen in a 37° C. water-bath, transfer to a tubecontaining 10 ml of Thaw Medium 1+Insulin (no Geneticin), spin downcells, resuspend cells in pre-warmed Thaw Medium 1+Insulin (noGeneticin), transfer resuspended cells to a T25 flask and culture in aCO₂ incubator at 37° C. overnight. The next day, replace the medium withfresh Thaw Medium 1+Insulin (no Geneticin), and continue growing culturein a CO₂ incubator at 37° C. until the cells are ready to be split. Atfirst passage, switch to Growth Medium 1B+10 μg/ml of Insulin (includesThaw Medium 1, Insulin, and Geneticin). Cells should be split beforethey reach complete confluence.

To passage the cells, rinse cells with phosphate buffered saline (PBS),and detach cells from the culture vessel with 0.25% Trypsin/EDTA. AddGrowth Medium 1B+10 μg/ml of Insulin (Includes Thaw Medium 1, Insulin,and Geneticin) and transfer to a tube, spin down the cells, then,resuspend cells and seed appropriate aliquots of cell suspension intonew culture vessels. Subcultivation ration: 1:5 to 1:10 weekly.

To freeze down the cells, rinse cells with phosphate buffered saline(PBS), and detach cells from culture vessel with Trypsin/EDTA. AddGrowth Medium 1B+10 μg/ml of Insulin (Includes Thaw Medium 1, Insulin,and Geneticin) and transfer to a tube, spin down cells, and resuspend infreezing medium (10% DMSO+90% FBS). Place at −80° C. overnight and placein liquid nitrogen the next day. Alternatively, vials may be placeddirectly in liquid nitrogen.

Functional Validation and Assay Performance

The following assays are designed for 96-well format. To perform theassay in different tissue culture formats, the cell number and reagentvolume should be scaled appropriately.

Materials Required but Not Supplied for Cell Culture

-   -   Thaw Medium 1 (BPS Bioscience #60187)+10 μg/ml of insulin    -   Growth Medium 1B (BPS Bioscience #79531)+10 μg/ml of insulin    -   Insulin Solution from Bovine Pancreas (Sigma-Aldrich #: 10516)        Materials Required But Not Supplied for Cellular Assay    -   H₂O₂: activator of Hippo pathway (activate MST kinases)    -   Insulin    -   Assay Medium: Thaw Medium 1 (BPS Cat. #60187)+10 μg/ml of        insulin    -   Insulin Solution from Bovine Pancreas (Sigma-Aldrich Cat #:        10516)    -   Okadaic acid (BPS bioscience #27047): activator of Hippo pathway        (activate MST kinases). Prepare 10 mM stock in DMSO.    -   96-well tissue culture plate or 96-well tissue culture-treated        white clear-bottom assay plate    -   ONE-Step™ Luciferase Assay System (BPS, Cat. #60690)    -   Luminometer        Mycoplasma Testing

The cell line has been screened using the PCR-based VenorGeM MycoplasmaDetection kit (Sigma-Aldrich) to confirm the absence of Mycoplasmaspecies.

Inhibition of TEAD Reporter Activity by Activator of Hippo Pathway inTEAD Reporter—MCF7 Cells

-   1) Harvest TEAD Reporter—MCF7 cells from culture in growth medium    and seed cells at a density of 35,000 cells per well into white    clear-bottom 96-well microplate in 45 μl of assay medium.-   2) Incubate cells at 37° C. in a CO₂ incubator for overnight.-   3) Dilute the activators (H₂O₂ or okadaic acid) stock in assay    medium. Add 5 μl of diluted activators to the wells. The final    concentration of DMSO in assay medium is 0.1%.-   4) Add 5 μl of assay medium with same concentration of DMSO without    activator to control wells.-   5) Add 50 μl of assay medium with DMSO to cell-free control wells    (for determining background luminescence).-   6) Set up each treatment in at least triplicate.-   7) Incubate cells at 37° C. in a CO₂ incubator for 5-6 hours.-   8) Perform luciferase assay using the ONE-Step™ Luciferase Assay    System following the protocol provided: Add 100 μl of ONE-Step™    Luciferase reagent per well and rock at room temperature for ˜15    minutes. Measure luminescence using a luminometer.-   9) Data Analysis: Obtain the background-subtracted luminescence by    subtracting the average background luminescence (cell-free control    wells) from the luminescence reading of all wells.

Certain compounds were tested in TEAD reporter assay, and in H226 andH28. The data are listed in Table 2 below. A: EC50<0.1 uM; B: 0.1uM≤EC50≤0.5 uM; C: EC50>0.5 uM.

TABLE 2 In vitro Data of Certain Exemplary Compounds. TEAD Reporter H226H28 Compound Assay EC50 (uM) EC50 (uM) EC50 (uM) I-27 A A C I-28 C C CI-29 A B C I-30 A A C I-31 A A C I-32 C C I-33 A A C I-34 C I-35 A A CI-36 A A C I-37 C B I-38 C C I-39 C C I-40 A A C I-41 C C I-42 A B I-43C C I-44 A A I-45 A A I-46 B B C I-47 C C I-48 C I-49 C C C I-50 C C CI-51 C C I-52 B B I-53 B B I-54 C C I-55 B B I-56 C C I-57 C C I-58 C CI-59 C C I-60 B A I-61 C C I-62 A A I-63 B C I-64 A A I-65 B C I-66 C CI-67 B B I-68 B C I-69 A A I-70 A A I-71 A A I-72 B A I-73 C C isomer 2of I-74 C C C isomer 1 of I-74 B A C isomer 2 of I-75 B A C isomer 1 ofI-75 C B C isomer 2 of I-76 B B C isomer 1 of I-76 C C isomer 2 of I-77C B C isomer 1 of I-77 A A C isomer 2 of I-78 A A C isomer 1 of I-78 C BC isomer 2 of I-79 C C isomer 1 of I-79 C C isomer 2 of I-80 C B isomer1 of I-80 B A isomer 2 of I-81 C C isomer 1 of I-81 C A isomer 2 ofI-103 A A C isomer 1 of I-103 C C isomer 2 of I-166 C A C isomer 1 ofI-166 C B isomer 2 of I-167 B A isomer 1 of I-167 A A C isomer 2 ofI-168 C isomer 1 of I-168 B A isomer 2 of I-169 C C isomer 1 of I-169 CC isomer 2 of I-170 A A C isomer 1 of I-170 C B isomer 2 of I-171 B A Cisomer 1 of I-171 C C isomer 2 of I-172 C C isomer 1 of I-172 C C isomer2 of I-173 C C isomer 1 of I-173 C C isomer 2 of I-174 C B isomer 1 ofI-174 C B isomer 2 of I-175 A A C isomer 1 of I-175 C B isomer 2 ofI-176 C C isomer 1 of I-176 C C isomer 2 of I-177 A A isomer 1 of I-177C B isomer 2 of I-178 C C isomer 1 of I-178 C C isomer 2 of I-179 C Cisomer 1 of I-179 C C isomer 2 of I-180 A A isomer 1 of I-180 C B isomer2 of I-181 B A isomer 1 of I-181 C B isomer 2 of I-182 B B isomer 1 ofI-182 A A isomer 2 of I-183 C C isomer 1 of I-183 B B isomer 2 of I-184C C isomer 1 of I-184 C C isomer 2 of I-185 C C isomer 1 of I-185 C Cisomer 2 of I-186 A B C isomer 1 of I-186 A A C isomer 2 of I-187 B B Cisomer 1 of I-187 C C isomer 2 of I-188 C C isomer 1 of I-188 A A Cisomer 2 of I-189 C B isomer 1 of I-189 A A C I-149 C B isomer 2 ofI-190 C C isomer 1 of I-190 A B isomer 2 of I-191 C B isomer 1 of I-191A A isomer 2 of I-192 B B isomer 1 of I-192 B B isomer 2 of I-193 C Cisomer 1 of I-193 C C 208 A A isomer 1 of I-316 C C isomer 2 of I-316 CC 211 A A 212 B A isomer 1 of I-318 B C isomer 2 of I-318 B B 217 C Cisomer 1 of I-321 C C isomer 2 of I-321 C C 220 A A 221 C C 222 A A 223C C 224 C C isomer 1 of I-326 A B isomer 2 of I-326 C C isomer 1 ofI-327 C C isomer 2 of I-327 B B isomer 2 of I-328 C C isomer 1 of I-328C C 231 A A isomer 1 of I-330 C C isomer 2 of I-330 C C 234 C A isomer 1of I-332 C C 236 C C isomer 2 of I-332 B C isomer 2 of I-333 B B isomer1 of I-333 B A isomer 2 of I-334 A A isomer 1 of I-334 A A isomer 2 ofI-335 B B isomer 1 of I-335 B C isomer 2 of I-336 C C isomer 1 of I-336C C 246 C C isomer 2 of I-337 C C isomer 1 of I-337 C C isomer 2 ofI-338 B A isomer 1 of I-338 B C 251 C C 252 C C isomer 1 of I-339 B Bisomer 2 of I-339 B B 255 C C 256 C A isomer 1 of I-341 A A isomer 2 ofI-341 C C 259 C C 260 C C isomer 1 of I-342 B C isomer 2 of I-342 C Bisomer 3 of I-342 C C isomer 4 of I-342 B B isomer 1 of I-343 A A isomer2 of I-343 B B isomer 3 of I-343 C C isomer 4 of I-343 C C 269 B C 270 CC 271 C C 272 C C 273 C C 274 B C 275 B C 276 B C 277 C C 278 C C 279 CC isomer 1 of I-344 C C isomer 2 of I-344 C C isomer 1 of I-345 C Cisomer 2 of I-345 C C 284 C C 285 C C 286 C C 287 C C 288 C C 289 B C290 B B isomer 1 of I-346 C C isomer 2 of I-346 C C 293 C C 294 C C 295C C 296 C C isomer 1 of I-347 B C isomer 2 of I-347 B B isomer 1 ofI-348 B B isomer 2 of I-348 B B isomer 1 of I-349 B C isomer 2 of I-349B C isomer 1 of I-350 C C isomer 2 of I-350 C B 305 A C isomer 1 ofI-351 A A isomer 2 of I-351 B B isomer 1 of I-352 B B isomer 2 of I-352A A isomer 1 of I-384 B B isomer 2 of I-384 A B I-386 B B I-387 C CI-388 C C I-389 C C isomer 1 of I-402 C B isomer 2 of I-402 C C I-393 CC I-394 B B I-395 C C I-397 C B isomer 1 of I-403 B B isomer 2 of I-403B B isomer 1 of I-404 C C isomer 2 of I-404 C C

Example 3: Mouse Pharmacokinetics Study

Formulated compounds were administered intravenously or orally viagavage to BALB/c mice. Typically, at 0.167, 0.5, 1, 2, 4, 6, 12, and 24hours post-dose, blood was collected and processed to plasma bycentrifugation and stored at −80° C. until analysis. Internal standardwas added to each sample prior to protein precipitation withacetonitrile or TCA. The precipitates were filtered through a filterplate and the samples were analyzed by LC/MS/MS. A standard curve wasprepared in plasma from typically from 1.0 ng/mL to 3000 ng/mL andprocessed in the same manner as the samples. Sample analysis wastypically performed on a suitable LC/MS/MS system fitted with ananalytical UPLC column and compounds eluted from the analytical columnwith a gradient from 30-95% 0.1% formic acid (v/v) in ACN: 0.1% formicacid (v/v) in water. Mass spectrometric detection of test compound andthe internal standard was performed by MR in positive mode. Thepharmacokinetics of each compound were analyzed by Phoenix WinNonlinsoftware (Pharsight, St. Louis, Mo.) via noncompartmental analysis.Compounds in Table 3 were dosed in 5% DMS/95% PEG400 at 10 mg/kg by oralgavage with Cmax and AUC_(0-last) summarized in Table 3. FIG. 4 depictspharmacokinetic (PK) properties of isomer 1 of compound I-186 followingdosing in BALB/c mice.

TABLE 3 Summary of Cmax and AUC_(0-last) Data Compound Cmax (ng/mL)AUC_(0-last) (ng * h/mL) P-5 246 397 Isomer 2 of I-12 23 48 Isomer 1 ofI-1 71.9 62 I-46 735 1137 isomer 1 of I-77 38 77 isomer 1 of I-186 110435 isomer 2 of I-187 11 20 isomer 2 of I-166 15 33 isomer 1 of I-188 1714 isomer 1 of I-189 36 86 I-62 345 368 I-203 63.3 275 I-69 1161 1241isomer 1 of I-191 48 114 isomer 2 of I-184 774 2519 I-208 318 226 I-2111247 1260 isomer 1 of I-333 211 492 isomer 2 of I-334 528 489 isomer 1of I-334 318 403 isomer 1 of I-341 55 119

Example 4. CTGF Data Analysis

NU/NU nude female mice obtained from Charles River Laboratories and weresubcutaneously injected with NCI-H226 (ATCC) human mesothelioma cells.Once tumors grew to an average size of 350-400 mm³, mice were randomizedinto each treatment group. NCI-H226 tumor bearing mice were treated byoral gavage with Vehicle (5% DMSO/95% PEG 400) or a TEAD inhibitor for atotal of 3 administrations. 4 hours post-third administration, mice wereeuthanized and tumors were collected for isolation of RNA forpharmacodynamic (PD) analysis.

RNA was extracted from the tumors utilizing the QIAZOL (Qiagen) lysisreagent, tissues were then homogenized for 10 minutes using TissueLyserII (Qiagen). Once sample disruption and digestion was complete,chloroform was added to each sample, the homogenate was separated intoaqueous and organic phases by centrifugation.

RNA was then isolated from samples using the KingFisher Flex automatedextraction system and MagMAX mirvana total RNA isolation kit.Manufacturer's recommended protocol for high-throughput isolation of RNAfrom tissue samples was followed for RNA extraction.

Expression of the YAP/TEAD-regulated gene, CCN2 that encodes CTFG(Connective Tissue Growth Factor), and the housekeeping gene, humanglyceraldehyde 3-phosphate dehydrogenase (GAPDH), were quantified byqRT-PCR analysis using the TaqMan Gene Expression Master Mix and TaqManprobes. CTGF and GAPDH cycle threshold (Ct) values for tumor cDNAsamples were determined, and CTGF expression was normalized to GAPDH asan internal control.

The relative CTGF mRNA expression levels for each treatment group fromtumor tissues were normalized to the vehicle control group. Forcomparisons between vehicle control and TEAD inhibitor treatment groups,an independent sample t-test was used for statistical analysis.

FIG. 5 depicts pharmacodynamic (PD) properties of isomer 2 of compoundI-12 and isomer 1 of compound I-186 using real-time PCR.

Example 5. Anti-Proliferation Assay

Individual cell lines were grown in medium according to supplierinstructions and seeded into 96-well plates at a density that ensuredlogarithmic growth over 72 hours. TEAD inhibitor compounds wereadministered to cells at a top concentration of 10 μm and subsequently a10 point 3-fold serial dilution was conducted. After 72 hours,proliferation was quantified using Cell TITERGLO™ (Promega, Inc.) andcompared to vehicle control. IC50 and EC50 values were generated usingXLFit curve fitting software.

FIG. 2 demonstrates inhibition of cell growth of an NF2 mutant cell lineby isomer 2 of compound I-12. The effect of isomer 2 of compound I-12 oncell proliferation is dependent on the presence of a Hippo/NF2 mutation.No effect is seen by isomer 2 of compound I-12 on the NF2 wild-type H28cell line.

FIG. 3 shows anti-proliferative effects of isomer 2 of compound I-12 asevaluated in a 3-day Cell TITERGLO™ assay. The cell lines were chosenbased on Cancer Dependency score and a sampling of known interactingoncogenes. Cell lines showing anti-proliferative effects followingtreatment with isomer 2 of compound I-12 and having EC50<0.2 μM or <1.0μM are indicated by boxes. EC50 values were calculated from inflectionpoints.

Example 6. In Vivo Inhibition of Tumor Growth

NCI-11226 In Vivo Efficacy Studies

6-8 week old nu/nu nude mice (CRL) were inoculated subcutaneously with5×106 NCI-H226 human mesothelioma tumor cells in the right flank. Tumorgrowth was monitored twice per week using vernier calipers and meantumor volume (MTV) was calculated using the formula V=W2×L/2.

When the MTV reached approximately 150-200 mm³, animals were randomizedinto treatment groups (n=8-10/group) and dosed per os (PO) on a onceeveryday (QD) schedule for 27-40 days with either Vehicle (5% DMSO+95%PEG 400) or TEAD inhibitors, such as isomer 2 of compound I-12, and/orisomer 1 of compound I-186.

Randomization and treatments started on Day 0 and % Tumor GrowthInhibition was calculated on the last day of the study (when the controlMTV reaches maximum allowable tumor volume), the following calculationwas performed.% TGI=100−[MTV treated/MTV control]×100

Tumor growth and body weight change were measured twice per week.

For comparisons between vehicle control and TEAD inhibitor treatmentgroups, an independent sample t-test was used for statistical analysis.

TABLE 5 Tumor Growth Inhibition (TGI) at Various Doses andAdministration Routes Dose Route of % TGI at Day of (mg/ admin- the endof calcu- Treatment kg) istration Schedule study lation Isomer 2 of 200PO QD 79.6 28 Compound I-12 Isomer 2 of 50 IP QD 82.6 28 Compound I-12Isomer 1 of 30 PO QD 49.9 40 Compound I-186 Isomer 1 of 30 PO QD 65.3 27Compound I-186 Isomer 1 of 75 PO QD 67.3 27 Compound I-186 Isomer 1 of75 PO Q2D 57.1 27 Compound I-186

FIGS. 6A-6B demonstrate anti-tumor activities of isomer 2 of compoundI-12 (6A) and isomer 1 of compound I-186 (6B) in an H226 mesotheliomaxenograft model. No effects were observed on body weights throughoutstudies. Kidneys at end of studies showed no signs of damage byhistopathology.

MSTO-211H1 In Vivo Efficacy Studies

6-8 week old SCID mice (CRL) were inoculated subcutaneously with 5×10⁶MSTO-211H human mesothelioma tumor cells in the right flank. Tumorgrowth was monitored twice per week using vernier calipers and meantumor volume (MTV) was calculated using the formula V=W2×L/2.

When the MTV reached approximately 150-200 mm³, animals were randomizedinto treatment groups (n=6-8/group) and dosed per os (PO) on a onceeveryday (QD) schedule for 22-25 days with either Vehicle (500 DMSO+9500PEG 400) or TEAD inhibitors, such as compound I-27.

Randomization and treatments started on Day 0 and % Tumor GrowthInhibition was calculated on the last day of the study (when the controlMTV reaches maximum allowable tumor volume), the following calculationwas performed.% TGI=100−[MTV treated/MTV control]×100

Tumor growth and body weight change were measured twice per week.

For comparisons between vehicle control and TEAD inhibitor treatmentgroups, an independent sample t-test was used for statistical analysis.

FIG. 7 demonstrates anti-tumor activities of isomer 2 of compound I-12and isomer 1 of compound I-186 in an MSTO-211H mesothelioma xenograftmodel. No effects were observed on body weights throughout studies.Kidneys at end of studies showed no signs of damage by histopathology.

Example 7: TEAD Selectivity Assays

The TEAD targeting selectivity profiles of the TEAD inhibitor compoundsdescribed herein can be determined by either or both of two exemplaryassays provided herein designed to monitor the interaction of TEADisoforms or variants, e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ IDNO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3(UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB IDQ15561 (SEQ ID NO: 4), and YAP1 or TAZ. While co-immunoprecipitationtechniques can be used to monitor protein-protein interactions, it isdifficult to increase the throughput based on the basic methodologyrequired. Accordingly, alternative but complementary assays are employedto monitor the interaction of the different TEAD isoforms or variants,e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2(UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594(SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4),and YAP1 (or TAZ).

The first exemplary assay is an in vitro biochemical fluorescentpolarization assay using recombinantly expressed and purifiedYAP-binding domains of individual TEAD isoforms and a fluorescentlylabeled peptide derived from the primary sequence of YAP1. (Bum-Erdeneet al., Cell Chem Biol. 2019 Mar. 21; 26(3):378-389.e13, the contents ofwhich are herein incorporated by reference in their entireties).Compounds are incubated with individual TEAD isoform proteins and thefluorescent peptide and potency is determined by quantifying thedisplacement of the peptide.

The second exemplary assay is a cell-based assay employing the splitluciferase reporter system (Hall et al., ACS Chem. Biol. 2012, 7, 11,1848-1857, the contents of which are herein incorporated by reference intheir entireties). Briefly, the YAP-binding domain of each TEAD isoformis transiently co-expressed with the TEAD-binding domain or either YAP1or TAZ in HEK293 cells and the proximity of the two chimeric gene fusionproducts is monitored by luciferase activity (Nouri et al. Cancers(Basel), 2019 Oct. 19; 11(10), the contents of which are hereinincorporated by reference in their entireties). Compounds that interferewith the interaction of a TEAD isoform and YAP1 (or TAZ) decrease theresulting luciferase activity relative to vehicle treated controls.Similar in process to the fluorescent polarization assay, these chimericgene fusions are recombinantly expressed in bacteria or insect cells andemployed as an in vitro biochemical assay with a similar luciferasereadout as the cell-based assay.

Example 8. Inhibition of Malignant Mesothelioma Tumor Cell Growth

The tumor cell growth inhibitory activity of the TEAD inhibitorsdescribed herein is evaluated in NCI-H2052 mesothelioma cell lineharboring a NF2 mutation. This cell line is selected, in part, based onits mutational status and the ability of a siRNA directed against YAP,TAZ or TEAD1-TEAD4 to inhibit cell proliferation. The nuclearlocalization of YAP at confluence is also taken into account. 10,000cells/well were plated in a 96-well black plate with clear flat bottomTC-Treated Imaging plate in regular medium with serum, which wasreplaced the day after with starvation medium containing 1% serum. Afterone day growth in the starvation medium, cells are incubated with TEADinhibitor compounds. The starting concentration is 30 μM and serialdilutions in DMSO and medium are performed until 0.1 μM to achieve afinal DMSO concentration of 0.5%. The cells are then allowed to grow for3 days, and then, EdU (Invitrogen, Molecular Probe) is added in eachwell at a final concentration of 10 μM and the cells are returned to theincubator for an additional 24 h. The starvation medium is removed and100 μl of PFA 4% containing Hoechst dye is added in each well to fix thecells. Plates are then incubated at room temperature for 15 min, washedtwice with PBS, and the cells permeabilized by adding 100 μl per well oftriton-100 containing 0.3% BSA. After 20 min, cells are washed with PBSand EdU detection is performed according to the instructions of themanufacturer. Image acquisition is performed, for example, using theImageXpress Micro and analyzed using the MetaXpress software (MolecularDevice).

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the application and appended claims rather than by thespecific embodiments that have been represented by way of example.

What is claimed is:
 1. A compound of Formula I′:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is C₁₋₆bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3methylene units of the chain are independently and optionally replacedwith —O—, —CH(OR)—, —CH(SR)—, —CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—,—N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—,—N(R)C(O)N(R)—, —S—, —SO—, —SO₂N(R)—, —(R)NSO₂—, —C(S)—, —C(S)O—,—OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—; Ring A is optionallysubstituted phenyl; Ring B is optionally substituted

R^(w) is -L-Y; L is a covalent bond or a bivalent C₁₋₈ saturated orunsaturated, straight or branched, hydrocarbon chain, wherein one, two,or three methylene units of L are optionally and independently replacedby cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—,—O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR)—,—N═N—, or —C(═N₂)—; Y is hydrogen, C₁₋₆ aliphatic optionally substitutedwith oxo, halogen, NO₂—, or CN, or a 3-10 membered monocyclic orbicyclic, saturated, partially unsaturated, or aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, andwherein said ring is substituted with 1-4 R^(e) groups; each R^(e) isindependently selected from -Q-Z, oxo, NO₂—, halogen, CN, or a C₁₋₆aliphatic optionally substituted with oxo, halogen, NO₂, or CN; Q is acovalent bond or a bivalent C₁₋₆ saturated or unsaturated, straight orbranched, hydrocarbon chain, wherein one or two methylene units of Q areoptionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—,—OC(O)—, —C(O)O—, —SO—, or —SO₂—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, or—SO₂N(R)—; Z is hydrogen or C₁₋₆ aliphatic optionally substituted withoxo, halogen, NO₂, or CN; and each R is independently —H or optionallysubstituted —C₁₋₆ aliphatic.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L¹ is C₁₋₆ bivalentstraight or branched hydrocarbon chain wherein 1, 2, or 3 methyleneunits of the chain are independently replaced with —O—, —CH(OR)—,—CH(N(R)₂)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—,—OC(O)N(R)—, —(R)NC(O)O—, or —N(R)C(O)N(R)—.
 3. The compound of claim 2,or a pharmaceutically acceptable salt thereof, wherein L¹ is —CH₂—. 4.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Ring A is phenyl, optionally substituted 1-2 times by halogen,—CN, —NO₂—, or —C₁₋₆ aliphatic substituted 0-6 times by halogen, —CN, or—NO₂.
 5. The compound of claim 4, or a pharmaceutically acceptable saltthereof, wherein Ring A is

R¹ is hydrogen, and R⁷ is —C₁₋₆ aliphatic substituted 0-6 times byhalogen.
 6. The compound of claim 1 or a pharmaceutically acceptablesalt thereof, wherein Ring B is


7. The compound of claim 6, or a pharmaceutically acceptable saltthereof, wherein Ring B is


8. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(w) is a


9. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (IX) or (X):


10. The compound of claim 9, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (IXa), (IXb), or (Xa):


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (XII):


12. The compound of claim 11, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (XIIa):


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (XIII) or (XIV):


14. The compound of claim 13, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (XIIIa) or (XIIIb):


15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (XV):


16. The compound of claim 15, or a pharmaceutically acceptable saltthereof, wherein the compound is of Formula (XVa) or (XVb):


17. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 18. The compound of claim 1,which is selected from:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim2, or a pharmaceutically acceptable salt thereof, wherein L¹ is C₁₋₆bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3methylene units of the chain are independently replaced with —N(R)—. 20.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L¹ is —CH₂—, —CH(CH₃)—, —NH—CH₂—, —NH—CH(CH₃)—, —C(O)—NH—, or—N(CH₃)—,


21. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Ring A is

wherein each of R¹ and R⁷ is independently —H, -halogen, —CN, —NO₂—,—C₁₋₆ aliphatic, or —O—C₁₋₆ aliphatic, wherein each of —C₁₋₆ aliphaticand —O—C₁₋₆ aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or6 times by -halogen, —CN, or —NO₂.
 22. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Ring A is


23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH₂N(CH₃)—,—NRC(O)CH═CHCH₂O—, —CH₂NRC(O)CH═CH—, —NRSO₂CH═CH—, —NRSO₂CH═CHCH₂—,—NRC(O)(C═N₂)—, —NRC(O)(C═N₂)C(O)—, —NRC(O)CH═CHCH₂N(CH₃)—,—NRSO₂CH═CH—, —NRSO₂CH═CHCH₂—, —NRC(O)CH═CHCH₂O—, —NRC(O)C(═CH₂)CH₂—,—CH₂NRC(O)—, —CH₂NRC(O)CH═CH—, —CH₂CH₂NRC(O)—, or—CH₂NRC(O)cyclopropylene-; and Y is hydrogen or C₁₋₆ aliphaticoptionally substituted with oxo, halogen, NO₂—, or CN.
 24. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein: L isa covalent bond; Y is a partially unsaturated 4-6 membered heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein said ring is substituted with 1-4 R^(e)groups; and each R^(e) is independently selected from oxo, NO₂—,halogen, and CN.